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Simple Summary: Non-small-cell lung cancer is the most prevalent type of lung cancer, with extensively characterized mutational spectra. Several biomarkers (such as EGFR, BRAF, KRAS gene mutations, etc.) have emerged as predictive and prognostic markers for lung cancer. Unfortunately, the quality of the available tumor biopsy and/or cytology material is not always adequate to perform the necessary molecular testing, prompting the search for alternatives. Cell-free DNA found in plasma is emerging as a highly promising avenue or a supplementary method for assessing the efficacy of cancer treatments. In this study, 51 Lithuanian females with non-small-cell lung cancer were studied. From each woman, two samples were obtained: lung tumor and plasma. Target mutations were identified in 38 out of 51 patients in tumor tissue samples, while in plasma samples, they were identified in only 10 patients' samples. Theoretically, cfDNA from plasma could be a superior tool for lung cancer diagnostics and the detection of early cancer stages. Therefore, further improvements in cfDNA extraction and detection methods from plasma are needed, including the development of superior detection kits and analysis tools. Non-small-cell lung cancer (NSCLC) is the most prevalent type of lung cancer, with extensively characterized mutational spectra. Several biomarkers (such as EGFR, BRAF, KRAS gene mutations, etc.) have emerged as predictive and prognostic markers for NSCLC. Unfortunately, the quality of the available tumor biopsy and/or cytology material is not always adequate to perform the necessary molecular testing, prompting the search for alternatives. Cell-free DNA (cfDNA) found in plasma is emerging as a highly promising avenue or a supplementary method for assessing the efficacy of cancer treatments. This is especially valuable in instances where conventional biopsy specimens, like formalin-fixed, paraffin-embedded (FFPE), or freshly frozen tumor tissues prove inadequate for conducting molecular pathology analyses subsequent to the initial diagnostic procedures. By leveraging cfDNA from plasma, clinicians gain an additional tool to gauge the effectiveness of cancer therapies, thereby enhancing their ability to optimize tailored treatment strategies. In this study, 51 Lithuanian females with NSCLC were analyzed, with adenocarcinoma being the predominant pathology diagnosis in 40 cases (78%). Target mutations were identified in 38 out of 51 patients (74.5%) in tumor tissue samples, while in plasma samples, they were identified in only 10 patients' samples (19.6%). Even though we did not have enough voluminous plasma samples in our study, gene mutations were detected in plasma from ten women, three of whom were diagnosed with early stages of lung cancer (stages I and II). For these patients, the following mutations were detected: deletion in exon 19 of the EGFR gene and single nucleotide polymorphisms in the TP53 and MET genes. All other women were diagnosed with stages III or IV of lung cancer. This indicates that the later stages of cancer contribute more cfDNA in plasma, making extraction less complicated. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer genomics and transcriptomics have revealed genes and pathways altered in several cancers. These studies have provided valuable information about cancer cells, their origin, oncogenic processes, and signaling pathways. An emerging challenge is to further characterize activity levels and interactions of pathways to develop a deeper understanding of how specific alterations in these interactions promote tumor growth. Drosophila with its sophisticated genetics has proved valuable in studying cooperative oncogenesis. Using Drosophila tumor models, we report a tumor cell-specific network comprising four pathways. We show that Wingless and effector caspase Dronc direct a signal amplification loop involving JNK and Hippo-effector Yorkie (Yki). Our studies provide evidence from in vivo studies regarding the organization of tumor-promoting oncogenic pathways, which may be useful in developing precise and effective approaches for pathway inhibition. These pathways are evolutionarily conserved from flies to humans, suggesting that findings from flies can be extrapolated to mammalian cancers. Cancer cells expand rapidly in response to altered intercellular and signaling interactions to achieve the hallmarks of cancer. Impaired cell polarity combined with activated oncogenes is known to promote several hallmarks of cancer, e.g., activating invasion by increased activity of Jun N-terminal kinase (JNK) and sustained proliferative signaling by increased activity of Hippo effector Yorkie (Yki). Thus, JNK, Yki, and their downstream transcription factors have emerged as synergistic drivers of tumor growth through pro-tumor signaling and intercellular interactions like cell competition. However, little is known about the signals that converge onto JNK and Yki in tumor cells and enable tumor cells to achieve the hallmarks of cancer. Here, using mosaic models of cooperative oncogenesis (RasV12,scrib−) in Drosophila, we show that RasV12,scrib− tumor cells grow through the activation of a previously unidentified network comprising Wingless (Wg), Dronc, JNK, and Yki. We show that RasV12,scrib− cells show increased Wg, Dronc, JNK, and Yki signaling, and all these signals are required for the growth of RasV12,scrib− tumors. We report that Wg and Dronc converge onto a JNK–Yki self-reinforcing positive feedback signal-amplification loop that promotes tumor growth. We found that the Wg–Dronc–Yki–JNK molecular network is specifically activated in polarity-impaired tumor cells and not in normal cells, in which apical-basal polarity remains intact. Our findings suggest that the identification of molecular networks may provide significant insights into the key biologically meaningful changes in signaling pathways and paradoxical signals that promote tumorigenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: In the present study, anticancer activity of pearl millet polyphenol-rich extract and encapsulated pearl millet polyphenol-rich fraction was investigated and compared using three cellular models of breast cancer in vitro. Proliferating and non-proliferating (drug-induced senescent) breast cancer cells were considered. Non-tumorigenic corresponding cells were used as control cells. Microencapsulation sensitized breast cancer cells to the treatment with pearl millet-based preparation. Cytotoxic effects were mediated by the induction of apoptotic cell death in the three breast cancer cell lines used. In one breast cancer cell line, encapsulated pearl millet extract also promoted cytotoxic autophagy. The usefulness of the microencapsulation approach was documented, especially in terms of the augmentation of anticancer effects of plant-derived compounds with limited bioavailability. Plant-derived polyphenols are bioactive compounds with potential health-promoting properties including antioxidant, anti-inflammatory, and anticancer activity. However, their beneficial effects and biomedical applications may be limited due to their low bioavailability. In the present study, we have considered a microencapsulation-based drug delivery system to investigate the anticancer effects of polyphenol-rich (apigenin, caffeic acid, and luteolin) fractions, extracted from a cereal crop pearl millet (Pennisetum glaucum), using three phenotypically different cellular models of breast cancer in vitro, namely triple negative HCC1806, ER-positive HCC1428, and HER2-positive AU565 cells. Encapsulated polyphenolic extract induced apoptotic cell death in breast cancer cells with different receptor status, whereas it was ineffective against non-tumorigenic MCF10F cells. Encapsulated polyphenolic extract was also found to be cytotoxic against drug-resistant doxorubicin-induced senescent breast cancer cells that were accompanied by increased levels of apoptotic and necrotic markers, cell cycle inhibitor p21 and proinflammatory cytokine IL8. Furthermore, diverse responses to the stimulation with encapsulated polyphenolic extract in senescent breast cancer cells were observed, as in the encapsulated polyphenolic extract-treated non-proliferating AU565 cells, the autophagic pathway, here cytotoxic autophagy, was also induced, as judged by elevated levels of beclin-1 and LC3b. We show for the first time the anti-breast cancer activity of encapsulated polyphenolic extract of pearl millet and postulate that microencapsulation may be a useful approach for potentiating the anticancer effects of phytochemicals with limited bioavailability. [ABSTRACT FROM AUTHOR]

Simple Summary: Performing multi-gene testing for detecting driver oncogene alterations is essential to avoid missing treatment opportunities with appropriate targeted therapies, including in cases with rare driver oncogene alterations. However, multi-gene testing has not been sufficiently implemented under the condition that the Oncomine Dx Target Test is only available in clinical settings in Japan. This study evaluated the recent status of multi-gene panel tests in our institution under the condition that both the Oncomine Dx Target Test and Amoy Dx® Pan Lung Cancer PCR panel were available. A favorable submission rate and success rate of multi-gene testing were shown, along with a favorable detection rate in recent clinical settings. As our practice of multi-gene testing has matured and the number of options for multi-gene testing with different characteristics has increased, it has become feasible to perform multi-gene testing on the majority of patients with non-small-cell lung cancer. Some multi-gene panel tests have been implemented in clinical settings to guide targeted therapy in non-small-cell lung cancer (NSCLC) in Japan. The current performance of multi-gene panel tests under the condition that the Oncomine Dx Target Test (ODxTT) and Amoy Dx® Pan Lung Cancer PCR panel (AmoyDx-multi) are available remains relatively unknown. We retrospectively reviewed consecutive patients with NSCLC, whose FFPE samples were considered for genetic testing. We assessed the submission rates, the success rates, and the driver oncogene detection rates of multi-gene panel tests. A total of 225 patients were histologically newly diagnosed with NSCLC or diagnosed with a recurrence of NSCLC without a previous multi-gene panel test at our institution. Among the 225 patients, the FFPE samples of 212 patients (94.2%) were submitted for multi-gene panel testing, including 191 samples (84.9%) for the ODxTT and 21 samples (9.3%) for the AmoyDx-multi. Among the 212 samples submitted to multi-gene panel tests, the success rate was 99.5% (211/212). The detection rate of driver oncogene alterations for all histologies was 52.4% (111/212), and that for adenocarcinoma was 69.7% (106/152). A favorable submission rate and success rate of multi-gene panel tests were shown, along with a favorable detection rate in recent clinical settings. [ABSTRACT FROM AUTHOR]

Simple Summary: Invasion of cancer into surrounding tissues is crucial for it to spread to other parts of the body, a process known as metastasis. The characteristics of cancer cells within tumors are significantly influenced by the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the primary cellular component of the TME and play a pivotal role in cancer progression, including growth, invasion, metastasis, therapy resistance, and immune suppression. Numerous factors mediating interactions between CAFs and cancer cells have been identified, such as growth factors, cytokines, and extracellular vesicles. Recent studies have highlighted the importance of direct contact between CAFs and cancer cells in facilitating cancer invasion and metastasis to distant organs. This review summarizes recent findings on the molecular and cellular mechanisms underlying this direct heterocellular adhesion, providing insights into how CAFs drive cancer invasion and metastasis. Cancer invasion is a requisite for the most malignant progression of cancer, that is, metastasis. The mechanisms of cancer invasion were originally studied using in vitro cell culture systems, in which cancer cells were cultured using artificial extracellular matrices (ECMs). However, conventional culture systems do not precisely recapitulate in vivo cancer invasion because the phenotypes of cancer cells in tumor tissues are strongly affected by the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are the most abundant cell type in the TME and accelerate cancer progression through invasion, metastasis, therapy resistance, and immune suppression. Thus, the reciprocal interactions between CAFs and cancer cells have been extensively studied, leading to the identification of factors that mediate cellular interactions, such as growth factors, cytokines, and extracellular vesicles. In addition, the importance of direct heterocellular adhesion between cancer cells and CAFs in cancer progression has recently been elucidated. In particular, CAFs are directly associated with cancer cells, allowing them to invade the ECM and metastasize to distant organs. In this review, we summarize the recent progress in understanding the molecular and cellular mechanisms of the direct heterocellular interaction in CAF-led cancer invasion and metastasis, with an emphasis on gastric cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Growing evidence indicates that p53-induced long noncoding (lnc) RNAs constitute an elaborate regulatory network that mediates and/or modulates p53 function and, thus, tumor suppression. p53-induced LINC01021 has been suggested to represent a negative feedback regulator of p53 protein stability under non-stress conditions. Furthermore, the loss of LINC01021 in p53-proficient colorectal cancer (CRC) cell lines results in increased sensitivity to DNA-damaging chemotherapeutics. In order to analyze whether LINC01021 affects the transcriptional program of p53 independently from the direct feedback regulation of p53, we studied the effect of CRISPR/Cas9-mediated abrogation of p53-induced LINC01021 transcription on genome-wide RNA expression changes after the activation of ectopic p53 in CRC cells by RNA-Seq analyses. Our results demonstrate diverse regulatory effects of LINC01021 on a subset of p53-regulated genes either via attenuated expression or altered transcript isoform usage. Taken together, our study provides a comprehensive framework and resource for further analyses of LINC01021 function downstream of p53. Background: Loss of the p53-inducible LINC01021 in p53-proficient CRC cell lines results in increased sensitivity to DNA-damaging chemotherapeutics. Here, we comprehensively analyze how LINC01021 affects the p53-induced transcriptional program. Methods: Using a CRISPR/Cas9-approach, we deleted the p53 binding site in the LINC01021 promoter of SW480 colorectal cancer cells and subjected them to RNA-Seq analysis after the activation of ectopic p53. RNA affinity purification followed by mass spectrometry was used to identify proteins associated with LINC01021. Results: Loss of the p53-inducibility of LINC01021 resulted in an ~1.8-fold increase in the number of significantly regulated mRNAs compared to LINC01021 wild-type cells after ectopic activation of p53. A subset of direct p53 target genes, such as NOXA and FAS, displayed significantly stronger induction when the p53-inducibility of LINC01021 was abrogated. Loss of the p53-inducibility of LINC01021 resulted in alternative splicing of a small number of mRNAs, such as ARHGAP12, HSF2, and LYN. Several RNA binding proteins involved in pre-mRNA splicing were identified as interaction partners of LINC01021 by mass spectrometry. Conclusions: Our results suggest that LINC01021 may restrict the extent and strength of p53-mediated transcriptional changes via context-dependent regulation of the expression and splicing of a subset of p53-regulated genes. [ABSTRACT FROM AUTHOR]

Background: Lipid droplets (LDs) as major lipid storage organelles are recently reported to be innate immune hubs. Perilipin-3 (PLIN3) is indispensable for the formation and accumulation of LDs. Since cancer patients show dysregulated lipid metabolism, we aimed to elaborate the role of LDs-related PLIN3 in oral squamous cell carcinoma (OSCC). Methods: PLIN3 expression patterns (n = 87), its immune-related landscape (n = 74) and association with B7-H2 (n = 51) were assessed by immunohistochemistry and flow cytometry. Real-time PCR, Western blot, Oil Red O assay, immunofluorescence, migration assay, spheroid-forming assay and flow cytometry were performed for function analysis. Results: Spotted LDs-like PLIN3 staining was dominantly enriched in tumor cells than other cell types. PLIN3high tumor showed high proliferation index with metastasis potential, accompanied with less CD3+CD8+ T cells in peripheral blood and in situ tissue, conferring immunosuppressive microenvironment and shorter postoperative survival. Consistently, PLIN3 knockdown in tumor cells not only reduced LD deposits and tumor migration, but benefited for CD8+ T cells activation in co-culture system with decreased B7-H2. An OSCC subpopulation harbored PLIN3highB7-H2high tumor showed more T cells exhaustion, rendering higher risk of cancer-related death (95% CI 1.285–6.851). Conclusions: LDs marker PLIN3 may be a novel immunotherapeutic target in OSCC. [ABSTRACT FROM AUTHOR]

Epstein–Barr virus (EBV) is a ubiquitous gammaherpesvirus etiologically associated with benign and malignant diseases. Since the pathogenic mechanisms of EBV are not fully understood, understanding EBV genetic diversity is an ongoing goal. Therefore, the present work describes the genetic diversity of the lytic gene BZLF1 in a sampling of 70 EBV-positive cases from southeastern Brazil. Additionally, together with the genetic regions previously characterized, the aim of the present study was to determine the impact of viral genetic factors that may influence EBV genetic diversity. Accordingly, the phylogenetic analysis of the BZLF1 indicated two main clades with high support, BZ-A and BZ-B (PP > 0.85). Thus, the BZ-A clade was the most diverse clade associated with the main polymorphisms investigated, including the haplotype Type 1 + V3 (p < 0.001). Furthermore, the multigene phylogenetic analysis (MLA) between BZLF1 and the oncogene LMP1 showed specific clusters, revealing haplotypic segregation that previous single-gene phylogenies from both genes failed to demonstrate. Surprisingly, the LMP1 Raji-related variant clusters were shown to be more diverse, associated with BZ-A/B and the Type 2/1 + V3 haplotypes. Finally, due to the high haplotypic diversity of the Raji-related variants, the number of DNA recombination-inducing motifs (DRIMs) was evaluated within the different clusters defined by the MLA. Similarly, the haplotype BZ-A + Raji was shown to harbor a greater number of DRIMs (p < 0.001). These results call attention to the high haplotype diversity of EBV in southeast Brazil and strengthen the hypothesis of the recombinant potential of South American Raji-related variants via the LMP1 oncogene. [ABSTRACT FROM AUTHOR]

Background: Long noncoding RNA (lncRNA) small nucleolar RNA host gene 6 (SNHG6) has been reported to be an oncogene in a variety of cancers. However, the role of SNHG6 and its associated mechanisms in Wilms' tumor progression remain largely unknown. Methods: The expression of SNHG6, microRNA-429 (miR-429), and FGF receptor substrates 2 (FRS2) messenger RNA (mRNA) was detected by quantitative real-time polymerase chain reaction. Cell proliferation was analyzed through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and plate colony assay. The apoptosis was assessed by flow cytometry. Cell glycolytic metabolism was analyzed through detecting the lactate dehydrogenase activity, glucose uptake, lactate production, and ATP level. The target relationship between miR-429 and SNHG6 or FRS2 was predicted by miRcode or Starbase and then validated by dual-luciferase reporter assay and RNA pull-down assay. Murine xenograft model was established to validate the function of SNHG6 in vivo. Results: The level of SNHG6 was elevated in Wilms' tumor tissues and cells, and SNHG6 played an oncogenic role to promote the proliferation and glycolysis and restrain the apoptosis of Wilms' tumor cells. MiR-429 was identified as a target of SNHG6, and miR-429 interference partly reversed the inhibitory effects induced by SNHG6 silencing on the malignant behaviors of Wilms' tumor cells. FRS2 mRNA bound to miR-429 in Wilms' tumor cells. SNHG6 upregulated the expression of FRS2 through acting as a sponge of miR-429. MiR-429-induced influences in Wilms' tumor cells were largely counteracted by the overexpression of FRS2. SNHG6 silencing suppressed the Wilms' tumor growth through miR-429/FRS2 axis in vivo. Conclusion: SNHG6 accelerated Wilms' tumor progression through regulating miR-429/FRS2 signaling in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Methylation-mediated gene silencing is closely related to the occurrence and development of human tumors. The euchromatic histone lysine methyltransferase 2 (EHMT2, also known as G9a) is highly expressed in many tumors and is generally considered to be an oncogene, which is associated with the poor outcome of many tumors. Combined immunotherapy and immune checkpoint blockade therapy also have good efficacy and certain safety. However, there are still many difficulties in the drugs targeting G9a, and the combined effect and safety of G9a with many drugs is still under study. This article aims to summarize the role and mechanism of G9a and its inhibitors in tumors in the past two years, and to understand the application prospect of G9a from the perspective of diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common malignant disease and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung cancers, and the probability of NSCLC gene mutations is high, with a wide variety of types. With the development of next-generation sequencing (NGS) detection technology, more and more patients with rare fusion gene mutations are detected. Neuregulin 1 (NRG1) gene is a rare oncogenic driver that can lead to activation of human epidermal growth factor receptor 3 (Her3/ErbB3) mediated pathway, resulting in tumor formation. In this article, we reported a case of mixed NSCLC with CRISPLD2-NRG1 fusion detected by RNA-based NGS, who responsed to Afatinib well after 1 month of treatment, and magnetic resonance imaging (MRI) showed shrinkage of intracranial lesions. Meanwhile, we also compiled previously reported NSCLC patients with NRG1 rare gene fusion mutation, in order to provide effective references for clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Lung cancer is still the leading cause of cancer death worldwide. Non-small cell lung cancer (NSCLC) is the main pathological type of lung cancer, accounting for about 80%. Approximately 30% of all patients with NSCLC have resectable early and middle stage disease at the time of diagnosis. Recently, the epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have made a major breakthrough in the adjuvant targeted therapy of EGFR-mutated resectable NSCLC, and are recommended by the guidelines for clinical use. In this review, we summarize the clinical research progress of perioperative adjuvant targeted therapy for EGFR-mutated resectable NSCLC, and discuss the key issues in the clinical researches. [ABSTRACT FROM AUTHOR]

Introduction: Cancer represents a significant global public health concern. In recent years, the incidence of cancer has been on the rise worldwide due to various factors, including diet, environment, and an aging population. Simultaneously, advancements in tumor molecular biology and genomics have led to a shift from systemic chemotherapy focused on disease sites and morphopathology towards precise targeted therapy for driver gene mutations. Therefore, we propose a comprehensive review aimed at exploring the research hotspots and directions in the field of Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant cancers over the past decade, providing valuable insights for cancer treatment strategies. Specifically, we aim to present an intellectual landscape using data obtained from the Web of Science (WoS) regarding KRAS mutation. Methods: Bibliometrix, VOSviewer, CiteSpace, and HistCite were employed to conduct scientometric analyses on national publications, influential authors, highly cited articles, frequent keywords, etc. Results: A total of 16,609 publications met the screening criteria and exhibited a consistent annual growth trend overall. Among 102 countries/regions, the United States occupied the vast majority share of the published volume. The journal Oncotarget had the highest circulation among all scientific publications. Moreover, the most seminal articles in this field primarily focus on biology and targeted therapies, with overcoming drug resistance being identified as a future research direction. Conclusion: The findings of the thematic analysis indicate that KRAS mutation in lung cancer, the prognosis following B-Raf proto-oncogene, serine/threonine kinase (BRAF) or rat sarcoma (RAS) mutations, and anti-epidermal growth factor receptor (EGFR)-related lung cancer are the significant hotspots in the given field. Considering the significant advancements made in direct targeting drugs like sotorasib, it is anticipated that interest in cancers associated with KRAS mutations will remain steadfast. [ABSTRACT FROM AUTHOR]

Cholangiocarcinoma (CCA) is characterized by rapid onset and high chance of metastasis. Therefore, identification of novel therapeutic targets is imperative. E26 transformation‐specific homologous factor (EHF), a member of the E26 transformation‐specific transcription factor family, plays a pivotal role in epithelial cell differentiation and cancer progression. However, its precise role in CCA remains unclear. In this study, through in vitro and in vivo experiments, we demonstrated that EHF plays a profound role in promoting CCA by transcriptional activation of glioma‐associated oncogene homolog 1 (GLI1). Moreover, EHF significantly recruited and activated tumor‐associated macrophages (TAMs) through the C‐C motif chemokine 2/C‐C chemokine receptor type 2 (CCL2/CCR2) axis, thereby remodeling the tumor microenvironment. In human CCA tissues, EHF expression was positively correlated with GLI1 and CCL2 expression, and patients with co‐expression of EHF/GLI1 or EHF/CCL2 had the most adverse prognosis. Furthermore, the combination of the GLI1 inhibitor, GANT58, and CCR2 inhibitor, INCB3344, substantially reduced the occurrence of EHF‐mediated CCA. In summary, our findings suggest that EHF is a potential prognostic biomarker for patients with CCA, while also advocating the therapeutic approach of combined targeting of GLI1 and CCL2/CCR2‐TAMs to inhibit EHF‐driven CCA development. [ABSTRACT FROM AUTHOR]

Objective: The aim of this case report is to investigate an uncommon presentation of Rosai–Dorfman–Destombes (RDD) disease, and discuss possible differential diagnoses and treatment options for this pathology. RDD is a rare disorder of histiocytes that typically presents in patients as painless cervical lymphadenopathy. However, this case involves a patient with the central nervous system (CNS) type of RDD who later developed cutaneous lesions. Method: Several differential diagnoses were examined, including hidradenitis suppurativa, pilonidal cyst and pressure ulcers. It is important to be able to exclude these diagnoses based on the presentation, patient demographic and wound location. Results: Biopsies verified the presence of RDD in the patient's suprasellar hypothalamic mass and skin lesions, confirming the patient had both CNS-RDD and cutaneous-RDD in the absence of lymphadenopathy. Conclusion: Recognising the unique manifestations of rare diseases such as RDD prevents delay of proper intervention and treatment. [ABSTRACT FROM AUTHOR]

The Xiphophorus melanoma receptor kinase gene, xmrk, is a bona fide oncogene driving melanocyte tumorigenesis of Xiphophorus fish. When ectopically expressed in medaka, it not only induces development of several pigment cell tumor types in different strains of medaka but also induces different tumor types within the same animal, suggesting its oncogenic activity has a transcriptomic background effect. Although the central pathways that xmrk utilizes to lead to melanomagenesis are well documented, genes and genetic pathways that modulate the oncogenic effect and alter the course of disease have not been studied so far. To understand how the genetic networks between different histocytes of xmrk‐driven tumors are composed, we isolated two types of tumors, melanoma and xanthoerythrophoroma, from the same xmrk transgenic medaka individuals, established the transcriptional profiles of both xmrk‐driven tumors, and compared (1) genes that are co‐expressed with xmrk in both tumor types, and (2) differentially expressed genes and their associated molecular functions, between the two tumor types. Transcriptomic comparisons between the two tumor types show melanoma and xanthoerythrophoroma are characterized by transcriptional features representing varied functions, indicating distinct molecular interactions between the driving oncogene and the cell‐type‐specific transcriptomes. Melanoma tumors exhibit gene signatures that are relevant to proliferation and invasion, while xanthoerythrophoroma tumors are characterized by expression profiles related to metabolism and DNA repair. We conclude the transcriptomic backgrounds, exemplified by cell‐type‐specific genes that are downstream of xmrk effected signaling pathways, contribute the potential to change the course of tumor development and may affect overall tumor outcomes. Research Highlights: Transcriptional background can affect oncogenic epidermal growth factor receptor (EGFR) mutation‐driven tumorigenesis and disease severeness in egfr transgenic medaka. [ABSTRACT FROM AUTHOR]

Glioma is often recurred after standard treatment due to its complex biological characteristics and the presence of glioma stem cells (GSCs). High-mobility group box 1 (HMGB1) can regulate the malignant progression of glioma through a variety of ways as an oncogene. This article reviews the relationship between HMGB1 gene and the prognosis of glioma patients, tumor pathological grading, GSCs, and the ways including non coding RNA pathway, autophagy pathway, tumor microenvironment, etc., in which HMGB1 gene regulates glioma, so as to provide the reference for the treatment of glioma. [ABSTRACT FROM AUTHOR]

Nuclear condensates have been shown to regulate cell fate control, but its role in oncogenic transformation remains largely unknown. Here we show acquisition of oncogenic potential by nuclear condensate remodeling. The proto-oncogene SS18 and its oncogenic fusion SS18-SSX1 can both form condensates, but with drastically different properties and impact on 3D genome architecture. The oncogenic condensates, not wild type ones, readily exclude HDAC1 and 2 complexes, thus, allowing aberrant accumulation of H3K27ac on chromatin loci, leading to oncogenic expression of key target genes. These results provide the first case for condensate remodeling as a transforming event to generate oncogene and such condensates can be targeted for therapy. One sentence summary: Expulsion of HDACs complexes leads to oncogenic transformation. [ABSTRACT FROM AUTHOR]

Simple Summary: In many tumor types, the development of personalized treatments has been allowed by the optimal molecular characterization of tumor cell genome alterations. In most carcinomas associated with human papillomaviruses (HPV), the integration of part of the viral genome into the tumor cell genome may lead to alterations of cancer-related genes located at the integration locus. In order to assess the overall frequency of such an event, we analyzed a large series of cases for which HPV integration sites had been determined. We found that 40% of the genes located at highly (≥3) recurrent HPV insertions corresponded to cancer-related genes. Moreover, about one-third of the genes targeted by HPV insertions correspond to actionable targets. These observations should lead to a more systematic analysis of HPV DNA integration patterns in HPV-associated carcinomas in order to identify highly specific tumor markers and develop personalized anti-tumor therapies. In HPV-associated carcinomas, some examples of cancer-related genes altered by viral insertion and corresponding to potential therapeutic targets have been described, but no quantitative assessment of these events, including poorly recurrent targets, has been reported to date. To document these occurrences, we built and analyzed a database comprised of 1455 cases, including HPV genotypes and tumor localizations. Host DNA sequences targeted by viral integration were classified as "non-recurrent" (one single reported case; 838 loci), "weakly recurrent" (two reported cases; 82 loci), and highly recurrent (≥3 cases; 43 loci). Whereas the overall rate of cancer-related target genes was 3.3% in the Gencode database, this rate increased to 6.5% in "non-recurrent", 11.4% in "weakly recurrent", and 40.1% in "highly recurrent" genes targeted by integration (p = 4.9 × 10−4). This rate was also significantly higher in tumors associated with high-risk HPV16/18/45 than other genotypes. Among the genes targeted by HPV insertion, 30.2% corresponded to direct or indirect druggable targets, a rate rising to 50% in "highly recurrent" targets. Using data from the literature and the DepMap 23Q4 release database, we found that genes targeted by viral insertion could be new candidates potentially involved in HPV-associated oncogenesis. A more systematic characterization of HPV/host fusion DNA sequences in HPV-associated cancers should provide a better knowledge of HPV-driven carcinogenesis and favor the development of personalize patient treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. Genetic alterations promote cancer development and its spread to distant sites. Medications that counteract the effects of these alterations/mutations, called targeted therapies, are used to treat CRC. Immunotherapy, another class of medications that promotes immune system mediated recognition and destruction of cancer cells, is used for treatment of a small subset of CRC patients. Here we review the current state of knowledge and ongoing research into biomarkers, targeted therapy, and immunotherapy for CRC treatment. Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. Although the overall incidence of CRC is decreasing, the incidence of young-onset CRC, characterized by a diagnosis of CRC before age 50, is increasing. Outcomes for CRC patients are improving, partly due to comprehensive molecular characterization of tumors and novel therapeutic strategies. Advances in genomic and transcriptomic analyses using blood- and tumor-tissue-based sequencing have facilitated identification of distinct tumor subtypes harboring unique biological characteristics and therapeutic vulnerabilities. These insights have led to the development and incorporation of targeted therapies and immunotherapy in CRC treatment. In this review, we discuss the molecular landscape and key oncogenes/tumor suppressors contributing to CRC tumorigenesis, metastasis, and therapeutic resistance. We also discuss personalized therapeutic strategies for subsets of CRC patients and provide an overview of evolving novel treatments being evaluated in clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-coding RNAs, particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are emerging as a driving force for lung cancer, the leading cause of cancer-related death. In this experimental work, we unveiled a novel competing endogenous RNA network (ceRNET) involving the lncRNA JPX, miR-378a-3p, and its downstream oncogenic targets in lung adenocarcinoma cells. First, a reverse expression pattern of JPX and miR-378a-3p was found in tumor tissues compared to normal lungs; subsequently, physical interaction between the molecules was demonstrated. Then, the boosting of either JPX or/and miR-378a-3p levels in lung cancer cells demonstrated the oncogenic role of JPX, the oncosuppressive function of the miRNA, and their functional relationship using an array of biological assays evaluating cell proliferation, migration, invasion, and 3D-spheroid formation. Finally, the ability of JPX to inhibit the silencing activity of miR-378a-3p toward its targets GLUT1, NRP1, YY1, and Wnt5a, and thus the contribution to lung cancer, was demonstrated. Lung cancer is the leading cause of cancer-related death worldwide. Non-coding RNAs are emerging as critical players for the onset and progression of cancer. Analyses of three different datasets revealed that the lncRNA JPX was overexpressed in adenocarcinoma tissues in comparison to normal lungs, as expected for an oncogene. Intriguingly, the predicted binding miR-378a-3p showed a significant inverse correlation with JPX expression. The lncRNA/miRNA physical interaction was validated by reporter vectors. Then, the oncogenic activity of JPX, the tumor-suppressive role of miR-378a-3p, and the contribution of their functional interaction to cancer hallmarks were demonstrated using assays for cell proliferation, migration, invasion, and 3D-spheroid formation. Finally, molecular circuits were investigated by boosting the expression of both JPX and miR-378a-3p, singularly and in combination, demonstrating that JPX counteracted miR-378a-3p silencing activity toward its oncogenic targets GLUT1, NRP1, YY1, and Wnt5a. Overall, the data unveil a novel ceRNET (competing endogenous RNA network), wherein JPX acts as a ceRNA by binding to miR-378a-3p, thus reducing the miRNA silencing activity toward its downstream targets, and eliciting oncogenic pathways driving lung cancer. The knowledge of the network may pave the way to develop new diagnostic panels, and innovative RNA-targeted and RNA-based therapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: We demonstrated that small interfering RNA replacement therapy using engineered exosomes exhibits promising effects in treating the peritoneal dissemination of ovarian cancer. Considering that patients with ovarian cancer routinely undergo omentectomy and that exosomes can be extracted from omental fibroblasts without difficulty, engineered exosomes can be used as siRNA delivery carriers for future molecular targeted therapies, ultimately resulting in the personalized treatment of patients with ovarian cancer. RNA interference is a powerful gene-silencing tool with potential clinical applications. However, its therapeutic use is challenging because suitable carriers are unavailable. Exosomes are stable small endogenous vesicles that can transport functional molecules to target cells, making them ideal small interfering RNA (siRNA) carriers. Herein, we elucidated the therapeutic potential of patient-derived exosomes as an siRNA carrier for ovarian cancer (OC) treatment. The exosomes were extracted from the culture medium of primary fibroblasts collected from the omentum of patients with OC during surgery. MET proto-oncogene, receptor tyrosine kinase (MET) was selected for gene silencing, c-Met siRNAs were synthesized and loaded into the exosomes (Met-siExosomes) via electroporation, and the treatment effect of the Met-siExosomes was assessed in vitro and in vivo. The Met-siExosomes downregulated the c-Met protein levels and inhibited OC cell proliferation, migration, and invasion. In xenograft experiments using SKOV3-13 and ES-2 cells, Met-siExosomes were selectively extracted from peritoneally disseminated tumors. Intraperitoneal treatment suppressed the c-Met downstream targets in cancer cells and prolonged mouse survival. The synthesized siRNAs were successfully and selectively delivered via the exosomes to intraperitoneally disseminated tumors. As patients with OC routinely undergo omentectomy and abundant fibroblasts can be easily collected from the omentum, patient-derived exosomes may represent a promising therapeutic siRNA carrier to treat OC. [ABSTRACT FROM AUTHOR]

Background: During mitosis the cell depends on proper attachment and segregation of replicated chromosomes to generate two identical progeny. In cancers defined by overexpression or dysregulation of the MYC oncogene this process becomes impaired, leading to genomic instability and tumor evolution. Recently it was discovered that the chromatin regulator WDR5—a critical MYC cofactor—regulates expression of genes needed in mitosis through a direct interaction with the master kinase PDPK1. However, whether PDPK1 and WDR5 contribute to similar mitotic gene regulation in MYC-overexpressing cancers remains unclear. Therefore, to characterize the influence of WDR5 and PDPK1 on mitotic gene expression in cells with high MYC levels, we performed a comparative transcriptomic analysis in neuroblastoma cell lines defined by MYCN-amplification, which results in high cellular levels of the N-MYC protein. Results: Using RNA-seq analysis, we identify the genes regulated by N-MYC and PDPK1 in multiple engineered CHP-134 neuroblastoma cell lines and compare them to previously published gene expression data collected in CHP-134 cells following inhibition of WDR5. We find that as expected N-MYC regulates a multitude of genes, including those related to mitosis, but that PDPK1 regulates specific sets of genes involved in development, signaling, and mitosis. Analysis of N-MYC- and PDPK1-regulated genes reveals a small group of commonly controlled genes associated with spindle pole formation and chromosome segregation, which overlap with genes that are also regulated by WDR5. We also find that N-MYC physically interacts with PDPK1 through the WDR5-PDPK1 interaction suggesting regulation of mitotic gene expression may be achieved through a N-MYC-WDR5-PDPK1 nexus. Conclusions: Overall, we identify a small group of genes highly enriched within functional gene categories related to mitotic processes that are commonly regulated by N-MYC, WDR5, and PDPK1 and suggest that a tripartite interaction between the three regulators may be responsible for setting the level of mitotic gene regulation in N-MYC amplified cell lines. This study provides a foundation for future studies to determine the exact mechanism by which N-MYC, WDR5, and PDPK1 converge on cell cycle related processes. [ABSTRACT FROM AUTHOR]

This study investigates Bacillus Calmette‐Guérin (BCG) as a potential treatment for hepatocellular carcinoma (HCC), a condition often associated with unfavorable treatment outcomes. Exploiting BCG's recognized immune‐boosting properties, preclinical trials are conducted using HCC mice, with a single subcutaneous dose of BCG administered post‐tumor formation. Results indicate that BCG treatment effectively diminishes tumor burden and extends survival in both male and female HCC mice. Positive influences on hepatic fibrosis and metabolism are observed, leading to a reduction in lipid levels. Spatial analysis underscores BCG's tumor‐specific effects, inducing the enrichment of metabolic pathways and inhibiting various cancer‐related pathways. Furthermore, BCG promotes immune cell infiltration, including CD4+, CD8+ T cells, and M1 macrophages, in both v‐akt murine thymoma viral oncogene homolog 1(AKT)/neutoblastoma RAS viral oncogene homolog (RAS) and β‐catenin positive HCC models. Interestingly, blocking T cells, trained immunity, and Interferon‐γ (IFN‐γ) function reverses BCG's anti‐HCC effects. In conclusion, BCG emerges as a promising treatment option for HCC, characterized by a favorable safety profile and efficacy in inhibiting fibrosis, improving metabolism, and engaging both trained immunity and T cells in therapeutic mechanisms. [ABSTRACT FROM AUTHOR]

Autophagy is a cellular self-degradation process that plays a crucial role in maintaining metabolic functions in cells and organisms. Dysfunctional autophagy has been linked to various diseases, including cancer. In cancer, dysregulated autophagy is closely associated with the development of cancer and drug resistance, and it can have both oncogenic and oncostatic effects. Research evidence supports the connection between m6A modification and human diseases, particularly cancer. Abnormalities in m6A modification are involved in the initiation and progression of cancer by regulating the expression of oncogenes and oncostatic genes. There is an interaction between m6A modification and autophagy, both of which play significant roles in cancer. However, the molecular mechanisms underlying this relationship are still unclear. m6A modification can either directly inhibit autophagy or promote its initiation, but the complex relationship between m6A modification, autophagy, and cancer remains poorly understood. Therefore, this paper aims to review the dual role of m6A and autophagy in cancer, explore the impact of m6A modification on autophagy regulation, and discuss the crucial role of the m6A modification-autophagy axis in cancer progression and treatment resistance. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin's lymphoma, characterized by remarkable molecular heterogeneity. This study evaluates the prevalence of MYC, BCL2, and BCL6 gene rearrangements among Iranian DLBCL patients. Method: This historical cohort study encompassed 152 patients drawn from six reference hospitals who participated in the research. Interphase dual-color break-apart fluorescence in situ hybridization (FISH) was applied to formalin-fixed paraffin-embedded DLBCL specimens categorized as "not otherwise specified" alongside 20 normal controls. Survival data was analyzed using the Kaplan-Meier method and the Log-Rank test. Results: Among the patients, 7 (4.8%), 4 (2.9%), and 15 (10.2%) exhibited MYC, BCL2, and BCL6 rearrangements, respectively. Additionally, 1.5% of the patients demonstrated double-hit (DH) characteristics with both MYC and BCL2 rearrangements, while no triple rearrangements were observed. The presence of rearrangements appeared to be independent of clinicopathological variables. Patients with rearrangements experienced reduced survival durations, with reductions of 26.6, 31.2, 9.1, and 34.2 months for MYC, BCL2, BCL6-rearranged, and DH tumors, respectively (P > 0.05). Adverse prognosis was associated with age, activated B-cell-like phenotype, disease stage, B symptoms, lactate dehydrogenase levels, and risk grouping according to the National Comprehensive Cancer Network (NCCN) International Prognostic Index. Conclusion: DLBCL cases featuring MYC, BCL2, and/or BCL6 translocations are relatively rare. Patients harboring these rearrangements tend to exhibit aggressive disease progression with shortened overall survival. However, these differences did not reach statistical significance, necessitating further research to validate the incorporation of such tests into the routine workup of DLBCL patients. [ABSTRACT FROM AUTHOR]

The discovery and subsequent research on the MET oncogene's role in cancer onset and progression have illuminated crucial insights into the molecular mechanisms driving malignancy. The identification of MET as the hepatocyte growth factor (HGF) receptor has paved the path for characterizing the MET tyrosine kinase activation mechanism and its downstream signaling cascade. Over the past thirty years, research has established the importance of HGF/MET signaling in normal cellular processes, such as cell dissociation, migration, proliferation, and cell survival. Notably, genetic alterations that lead to the continuous activation of MET, known as constitutive activation, have been identified as oncogenic drivers in various cancers. The genetic lesions affecting MET, such as exon skipping, gene amplification, and gene rearrangements, provide valuable targets for therapeutic intervention. Moreover, the implications of MET as a resistance mechanism to targeted therapies emphasize the need for combination treatments that include MET inhibitors. The intriguing "flare effect" phenomenon, wherein MET inhibition can lead to post-treatment increases in cancer cell proliferation, underscores the dynamic nature of cancer therapeutics. In human tumors, increased protein expression often occurs without gene amplification. Various mechanisms may cause an overexpression: transcriptional upregulation induced by other oncogenes; environmental factors (such as hypoxia or radiation); or substances produced by the reactive stroma, such as inflammatory cytokines, pro-angiogenic factors, and even HGF itself. In conclusion, the journey to understanding MET's involvement in cancer onset and progression over the past three decades has not only deepened our knowledge, but has also paved the way for innovative therapeutic strategies. Selective pharmacological inactivation of MET stands as a promising avenue for achieving cancer remission, particularly in cases where MET alterations are the primary drivers of malignancy. [ABSTRACT FROM AUTHOR]

Super enhancers (SEs) consist of clusters of enhancers, harboring an unusually high density of transcription factors, mediator coactivators and epigenetic modifications. SEs play a crucial role in the maintenance of cancer cell identity and promoting oncogenic transcription. Super enhancer lncRNAs (SE-lncRNAs) refer to either transcript from SEs locus or interact with SEs, whose transcriptional activity is highly dependent on SEs. Moreover, these SE-lncRNAs can interact with their associated enhancer regions in cis and modulate the expression of oncogenes or key signal pathways in cancers. Inhibition of SEs would be a promising therapy for cancer. In this review, we summarize the research of SE-lncRNAs in different kinds of cancers so far and decode the mechanism of SE-lncRNAs in carcinogenesis to provide novel ideas for the cancer therapy. [ABSTRACT FROM AUTHOR]

Cellular membranes serve as an epicentre combining extracellular and cytosolic components with membranous effectors, which together support numerous fundamental cellular signalling pathways that mediate biological responses. To execute their functions, membrane proteins, lipids and carbohydrates arrange, in a highly coordinated manner, into well‐defined assemblies displaying diverse biological and biophysical characteristics that modulate several signalling events. The loss of membrane homeostasis can trigger oncogenic signalling. More recently, it has been documented that select membrane active dietaries (MADs) can reshape biological membranes and subsequently decrease cancer risk. In this review, we emphasize the significance of membrane domain structure, organization and their signalling functionalities as well as how loss of membrane homeostasis can steer aberrant signalling. Moreover, we describe in detail the complexities associated with the examination of these membrane domains and their association with cancer. Finally, we summarize the current literature on MADs and their effects on cellular membranes, including various mechanisms of dietary chemoprevention/interception and the functional links between nutritional bioactives, membrane homeostasis and cancer biology. [ABSTRACT FROM AUTHOR]

Simple Summary: The therapeutic scenario of early-stage (ES) non-small cell lung cancer (NSCLC) is rapidly evolving. Precision medicine, including both targeted therapy and immunotherapy, has recently entered the clinical practice of neoadjuvant and adjuvant settings. However, only a few data are available about oncogene addiction of ES tumors. In this study, we determined the prevalence of the main lung cancer actionable alterations in a consecutive monocentric cohort of ES-NSCLC. We found that the prevalence of targetable alterations was similar between ES and advanced NSCLC, with a significant enrichment in MET exon 14 skipping alterations in ES-NSCLC. Our results can support the role of a biomarker testing strategy to improve the management of ES lung cancer patients. Early-stage (ES) non-small cell lung cancer (NSCLC) is diagnosed in about 30% of cases. The preferred treatment is surgery, but a significant proportion of patients experience recurrence. Neoadjuvant and adjuvant chemotherapy has a limited clinical benefit. EGFR tyrosine kinase inhibitors and immunotherapy have recently opened new therapeutic scenarios. However, only a few data are available about the ES-NSCLC molecular landscape and the impact of oncogene addiction on therapy definition. Here, we determined the prevalence of the main lung cancer driver alterations in a monocentric consecutive cohort. Molecular analysis was performed on 1122 cases, including 368 ES and 754 advanced NSCLC. The prevalence of actionable alterations was similar between early and advanced stages. ES-NSCLC was significantly enriched for MET exon-14 skipping alterations and presented a lower prevalence of BRAF p.(V600E) mutation. PD-L1 expression levels, evaluated according to actionable alterations, were higher in advanced than early tumors harboring EGFR, KRAS, MET alterations and gene fusions. Taken together, these results confirm the value of biomarker testing in ES-NSCLC. Although approved targeted therapies for ES-NSCLC are still limited, the identification of actionable alterations could improve patients' selection for immunotherapy, favoring the enrollment in clinical trials and allowing a faster treatment start at disease recurrence. [ABSTRACT FROM AUTHOR]

Simple Summary: Extracellular signal-regulated kinase 3 (ERK3) is a member of the atypical mitogen-activated protein kinase (MAPK) subfamily. While it remains largely unknown regarding the upstream stimuli and regulators for its kinase activation, ERK3 has been shown to play important roles in physiological processes and cancers. This review discusses the growing body of work that unveils the roles for ERK3 in regulating cell growth, migration and invasion, as well as cancer growth and progression. In addition, it provides important insights on the molecular regulation of ERK3 expression and activity and its implications in different signaling pathways in cancers. Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK) whose structural and regulatory features are distinct from those of conventional MAPKs, such as ERK1/2. Since its identification in 1991, the regulation, substrates and functions of ERK3 have remained largely unknown. However, recent years have witnessed a wealth of new findings about ERK3 signaling. Several important biological functions for ERK3 have been revealed, including its role in neuronal morphogenesis, inflammation, metabolism, endothelial cell tube formation and epithelial architecture. In addition, ERK3 has been recently shown to play important roles in cancer cell proliferation, migration, invasion and chemoresistance in multiple types of cancers. Furthermore, accumulating studies have uncovered various molecular mechanisms by which the expression level, protein stability and activity of ERK3 are regulated. In particular, several post-translational modifications (PTMs), including ubiquitination, hydroxylation and phosphorylation, have been shown to regulate the stability and activity of ERK3 protein. In this review, we discuss recent findings regarding biochemical and cellular functions of ERK3, with a main focus on its roles in cancers, as well as the molecular mechanisms of regulating its expression and activity. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer (BC) is the most common malignancy and the leading cause of cancer mortality in women. It is possible that signals arising from the gut microbiome are protective in BC. We used common drugs designed to turn on pathways to mimic one major signal coming from gut microbes, namely bile acids. Taking advantage of a drug called Ocaliva, which is commercially available for another disease, we repurposed this drug to test its anti-cancer potential. Ocaliva worked on a specific protein target called FXR to reduce tumor growth and killed cancer cells. In contrast, a similar drug that targets a different protein called TGR5 was not effective in killing cancer cells. Taken together, findings suggest that using Ocaliva or other bile acid signals derived from the gut microbiome to target the protein FXR could be an important new therapeutic strategy for individuals with aggressive BC. Bariatric surgery is associated with improved outcomes for several cancers, including breast cancer (BC), although the mechanisms mediating this protection are unknown. We hypothesized that elevated bile acid pools detected after bariatric surgery may be factors that contribute to improved BC outcomes. Patients with greater expression of the bile acid receptor FXR displayed improved survival in specific aggressive BC subtypes. FXR is a nuclear hormone receptor activated by primary bile acids. Therefore, we posited that activating FXR using an established FDA-approved agonist would induce anticancer effects. Using in vivo and in vitro approaches, we determined the anti-tumor potential of bile acid receptor agonism. Indeed, FXR agonism by the bile acid mimetic known commercially as Ocaliva ("OCA"), or Obeticholic acid (INT-747), significantly reduced BC progression and overall tumor burden in a pre-clinical model. The transcriptomic analysis of tumors in mice subjected to OCA treatment revealed differential gene expression patterns compared to vehicle controls. Notably, there was a significant down-regulation of the oncogenic transcription factor MAX (MYC-associated factor X), which interacts with the oncogene MYC. Gene set enrichment analysis (GSEA) further demonstrated a statistically significant downregulation of the Hallmark MYC-related gene set (MYC Target V1) following OCA treatment. In human and murine BC analyses in vitro, agonism of FXR significantly and dose-dependently inhibited proliferation, migration, and viability. In contrast, the synthetic agonism of another common bile acid receptor, the G protein-coupled bile acid receptor TGR5 (GPBAR1) which is mainly activated by secondary bile acids, failed to significantly alter cancer cell dynamics. In conclusion, agonism of FXR by primary bile acid memetic OCA yields potent anti-tumor effects potentially through inhibition of proliferation and migration and reduced cell viability. These findings suggest that FXR is a tumor suppressor gene with a high potential for use in personalized therapeutic strategies for individuals with BC. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most common cancer in women and one of the deadliest. While survival rates for patients with breast cancer have seen notable improvements in recent decades, current treatment strategies still face significant limitations, especially for patients with aggressive, therapy-resistant, and metastatic breast cancers. For this reason, it is important to identify new targets in order to develop more effective therapeutic strategies. The N-myc downstream regulated gene family (NDRGs), comprising NDRG1, NDRG2, NDRG3, and NDRG4, has been previously described as tumor suppressors. However, recent findings challenge this perception, particularly for NDRG1, which has demonstrated a critical role in driving tumor growth and metastasis in aggressive forms of breast cancer. In this review, we discuss the role of the NDRG family members in breast cancer, which is supported by analyses of genomic and transcriptomic data from various independent breast cancer patient cohorts. The N-myc downstream regulated gene family (NDRGs) includes four members: NDRG1, NDRG2, NDRG3, and NDRG4. These members exhibit 53–65% amino acid identity. The role of NDRGs in tumor growth and metastasis appears to be tumor- and context-dependent. While many studies have reported that these family members have tumor suppressive roles, recent studies have demonstrated that NDRGs, particularly NDRG1 and NDRG2, function as oncogenes, promoting tumor growth and metastasis. Additionally, NDRGs are involved in regulating different signaling pathways and exhibit diverse cellular functions in breast cancers. In this review, we comprehensively outline the oncogenic and tumor suppressor roles of the NDRG family members in breast cancer, examining evidence from in vitro and in vivo breast cancer models as well as tumor tissues from breast cancer patients. We also present analyses of publicly available genomic and transcriptomic data from multiple independent cohorts of breast cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Biomarker-guided therapies offer the possibility for targeted cancer therapies. For gastric cancer, HER2 plays a pivotal role. To date, with trastuzumab and trastuzumab-deruxtecan, two HER2-targeting options exist for the treatment of metastatic HER2-positive gastric cancer. However, these therapies rarely lead to long-lasting results as resistance mechanisms and heterogeneity limit their success. This review gives an overview of the current standard-of-care treatment of HER2-positive gastric cancer and new developments in the field. Despite a decreasing incidence in Western countries, gastric cancer is among the most common cancer subtypes globally and is associated with one of the highest tumor-related mortality rates. Biomarkers play an increasing role in the treatment against gastric cancer. HER2 was one of the first biomarkers that found its way into clinical practice. Since the ToGA trial, trastuzumab has been part of first-line palliative chemotherapy in metastatic or unresectable gastric cancer. HER2-targeting agents, such as the tyrosine kinase inhibitor lapatinib, the antibody drug conjugate (ADC) trastuzumab-emtansine or dual HER2 inhibition (pertuzumab and trastuzumab), have been investigated in the second-line setting but led to negative study results. More recently, the ADC trastuzumab-deruxtecan was authorized after the failure of trastuzumab-based treatment. However, further improvements in HER2-directed therapy are required as resistance mechanisms and HER2 heterogeneity limit the existing treatment options. This review aims to give an overview of the current standard-of-care HER2-directed therapy in gastric cancer, as well as its challenges and future developments. [ABSTRACT FROM AUTHOR]

Simple Summary: The dramatic improvement in the prognosis of patients with advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) became possible thanks to the advent of EGFR-tyrosine kinase inhibitors (EGFR-TKIs). In a subgroup of EGFR mutations, known as uncommon (ucEGFRmuts) and rare, NSCLC-mutated patients show, most of the time, lower EGFR-TKIs sensitivity than most common mutations, making this a great clinical point of discussion. Here, we summarized recent data about EGFR exon 20 insertion-positive NSCLC patients and Phase 3 trials ongoing, with a specific focus on the PAPILLON study. Uncommon (ucEGFRmuts) and rare epidermal growth factor receptor (EGFR) mutations account for 10–15% of diagnosed cases and consist of a heterogeneous group represented by several clusters within exons 18–21 (e.g., exon 18 point mutations, exon 21 L861X, exon 20 S768I), as well as exon 20 insertions (Ex20ins). Their incidence is under molecular and clinical investigation following recent findings that reported an increase of sensitivity and specificity of next-generation sequencing (NGS) methods. Consequently, their detection allows for the selection of emerging treatment options to significantly improve patients' outcomes in these particular subgroups of EGFR-mutated advanced non-small cell lung cancer (NSCLC). Specifically, this commentary is focused on the notable progress of the Phase 3 PAPILLON study that showed primary efficacy results from amivantamab, a bispecific antibody with specific binding and affinity to extracellular domains of EGFR and MET, plus chemotherapy in the first-line setting for EGFR exon 20 insertion–mutated advanced or metastatic NSCLC patients, as compared with chemotherapy alone, thus becoming the new standard of care in this group of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: While both the fields of cancer metastasis research and cancer immunology have been heavily investigated, their combination—the immunology of metastasis—is underrepresented given the fact that metastasis is responsible for up to 90% of cancer deaths. Additionally, evading detection by the immune system is a key prerequisite for the spread of tumor cells to distant organs. In this review, we explore the connections between a master regulator of metastasis, MACC1, and both its direct and indirect links with immunological processes. Specifically, we highlight MACC1-induced alterations of signaling pathways and secreted factors and how this translates into changed immunological outcomes including effects on immune cell infiltration, activity, and their regulation through immunological checkpoints. Metastasis remains the most critical factor limiting patient survival and the most challenging part of cancer-targeted therapy. Identifying the causal drivers of metastasis and characterizing their properties in various key aspects of cancer biology is essential for the development of novel metastasis-targeting approaches. Metastasis-associated in colon cancer 1 (MACC1) is a prognostic and predictive biomarker that is now recognized in more than 20 cancer entities. Although MACC1 can already be linked with many hallmarks of cancer, one key process—the facilitation of immune evasion—remains poorly understood. In this review, we explore the direct and indirect links between MACC1 and the mechanisms of immune escape. Therein, we highlight the signaling pathways and secreted factors influenced by MACC1 as well as their effects on the infiltration and anti-tumor function of immune cells. [ABSTRACT FROM AUTHOR]

Glypicans are linked to various aspects of neoplastic behavior, and their therapeutic value has been proposed in different cancers. Here, we have systematically assessed the impact of GPC4 on cancer progression through functional genomics and transcriptomic analyses across a broad range of cancers. Survival analysis using TCGA cancer patient data reveals divergent effects of GPC4 expression across various cancer types, revealing elevated GPC4 expression levels to be associated with both poor and favorable prognoses in a cancer-dependent manner. Detailed investigation of the role of GPC4 in glioblastoma and non-small cell lung adenocarcinoma by genetic perturbation studies displays opposing effects on these cancers, where the knockout of GPC4 with CRISPR/Cas9 attenuated proliferation of glioblastoma and augmented proliferation of lung adenocarcinoma cells and the overexpression of GPC4 exhibited a significant and opposite effect. Further, the overexpression of GPC4 in GPC4-knocked-down glioblastoma cells restored the proliferation, indicating its mitogenic effect in this cancer type. Additionally, a survival analysis of TCGA patient data substantiated these findings, revealing an association between elevated levels of GPC4 and a poor prognosis in glioblastoma, while indicating a favorable outcome in lung carcinoma patients. Finally, through transcriptomic analysis, we attempted to assign mechanisms of action to GPC4, as we find it implicated in cell cycle control and survival core pathways. The analysis revealed upregulation of oncogenes, including FGF5, TGF-β superfamily members, and ITGA-5 in glioblastoma, which were downregulated in lung adenocarcinoma patients. Our findings illuminate the pleiotropic effect of GPC4 in cancer, underscoring its potential as a putative prognostic biomarker and indicating its therapeutic implications in a cancer type dependent manner. [ABSTRACT FROM AUTHOR]

Background: The standard of care in newly diagnosed metastatic non‐small cell lung cancer (NSCLC) is to test for aberrations in three genes for driver mutations – ALK, ROS1 and epidermal growth factor receptor (EGFR) – and also for immunohistochemistry to be performed for programmed death‐ligand 1 expression level. Next‐generation sequencing (NGS), with or without RNA fusion testing, is increasingly used in standard clinical practice to identify patients with potentially actionable mutations. Stratification of NGS mutation tiers is currently based on the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) Tiers I–V and X. Aim: Our aim was to analyse NSCLC tumour samples for the prevalence of Tiers I–V mutations to establish guidance for current and novel treatments in patients with metastatic disease. Methods: NGS was performed employing the Oncomine Precision Assay (without RNA fusion testing) that interrogates DNA hotspot variants across 45 genes to screen 210 NSCLC tissue samples obtained across six Sydney hospitals between June 2021 and March 2022. Results: In our cohort, 161 of 210 (77%) had at least one gene mutation identified, with 41 of 210 (20%) having two or more concurrent mutations. Tier I mutations included 42 of 210 (20%) EGFR mutations (EIA) and five of 210 (3%) MET exon 14 skipping mutations (EIB). Non‐Tier I variants included 22 of 210 (11%) KRAS G12C hotspot mutations (EIIB), with a further 47 of 210 (22%) having non‐G12C KRAS (EX) mutations. NGS testing revealed an additional 15% of cases with Tier II ESCAT mutations in NSCLC. Forty‐six percent of patients also demonstrated potential Tier III and IV mutations that are currently under investigation in early‐phase clinical trials. Conclusions: In addition to identifying patients with genomic alterations suitable for clinically proven standard‐of‐care therapeutic options, the 45‐gene NGS panel has significant potential in identifying potentially actionable non‐Tier 1 mutations that may become future standard clinical practice in NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: Gastric cancer (GC) is prevalent as one of the most common malignant tumors globally, with a particularly high incidence in China. The role of UBE2L3 in the initiation and progression of various cancers has been well documented, but its specific significance in GC is not yet fully elucidated. The objective of this study is to examine the expression and importance of UBE2L3 in human gastric cancer tissues. Methods: Immunohistochemical staining and survival analysis were conducted on 125 cases of GC. Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to assess the expression of UBE2L3 in GC cell lines. Cell lines with UBE2L3 knockdown and overexpression were cultured through lentivirus transfection and subsequently assessed using Western blot analysis. The involvement of UBE2L3 in the proliferation, invasion, and apoptosis of GC cells was confirmed through in vitro experiments, and its capacity to facilitate tumor growth was also validated in in vivo studies. Results: The up-regulation of UBE2L3 expression was observed in GC, and its high expression was found to be significantly associated with the degree of differentiation (χ2 = 6.153, P = 0.0131), TNM stage (χ2 = 6.216, P = 0.0447), and poor overall survival. In vitro, UBE2L3 has been shown to enhance functions in GC cell lines, such as promoting proliferation and invasion, and inhibiting apoptosis. In vivo experiments have validated the role of UBE2L3 in promoting tumor growth. Conclusions: The findings of our study demonstrate the significant involvement of UBE2L3 in the pathogenesis and advancement of gastric cancer, suggesting its potential as a therapeutic target. [ABSTRACT FROM AUTHOR]

Background: It is difficult to predict gene mutations individually based on clinical background alone. Tumor markers may help to predict each gene mutation. Identifying tumor markers that can predict gene mutation will facilitate timely genetic testing and intervention. Methods: We selected 134 cases of advanced or recurrent ALK-positive and 172 cases of advanced or recurrent EGFR-positive lung cancer from our clinical database. The cutoff values for the tumor markers were defined as 5.0 ng/mL or higher for carcinoembryonic antigen (CEA) and 3.5 ng/mL or higher for soluble fragment of cytokeratin 19 (CYFRA21-1) in accordance with the institutional standards. A positive CYFRA21-1:CEA ratio was defined as 0.7 or higher. Results: The CEA-positivity rate was 49% for ALK-positive lung cancers and 73% for EGFR-positive lung cancers, which was significantly different (p < 0.001). The CYFRA21-1 positivity rate was significantly higher in ALK-positive lung cancer (36%) compared with EGFR-positive lung cancer (23%) (p = 0.034). The median CYFRA21-1:CEA ratio was 0.395 for the ALK group, which was significantly higher compared with 0.098 for the EGFR group (p < 0.001). These trends were similar when excluding histology other than adenocarcinoma. The median time-to-treatment failure (TTF) for initial tyrosine kinase inhibitor (TKI) therapy was 308 days for the high CYFRA21-1:CEA ratio group and 617 days for the low CYFRA21-1:CEA ratio group for ALK-positive lung cancer (p = 0.100). Conclusions: A higher proportion of patients with ALK-positive lung cancer were CYFRA21-1 positive and had higher CYFRA21-1:CEA ratios compared with EGFRpositive lung cancer patients. [ABSTRACT FROM AUTHOR]

Coagulation factor VIII (FVIII) is an essential cofactor in the coagulation cascade, encoded by the F8 gene on the long arm of chromosome X (Xq28). FVIII is normally circulated in complex with Von Willebrand factor (VWF) and has relevant emerging ex-tracoagulative functions. Dysregulation of FVIII is associated with tumor progression, and could be used as a novel biomarker for tumor screening and monitoring. In breast cancer, bladder cancer, colorectal carcinoma, esophageal carcinoma, hepatocellular carcinoma and lung cancer, F8 is regarded as an oncogene. In coronary heart disease, hemophilia A and liver disease, F8 dysregulation has been recognized as a potential bi-omarker for disease diagnosis and prognosis. However, the basis of these differential expression levels remains to be understood. In this review, which is a mixture of literature review and bioinformatics analysis we described the biological functions and characteristics of FVIII, and also its expression level in non-malignant disorders and various cancers. [ABSTRACT FROM AUTHOR]

* Context.--Unlike B-cell acute lymphoblastic leukemia/lymphoma (ALL/LBL), there have been few therapeutic advances in T-cell ALL (T-ALL)/LBL, an aggressive ALL/LBL subtype. Objective.--To perform a focused tissue array study to elucidate tumor markers of therapeutic potential in T-ALL/LBL. Design.--Using immunohistochemistry, we evaluated expression of leukemic antigens of interest, specifically CCchemokine receptor 4 (CCR4), among others, on available remnant diagnostic material, including tumor tissue slides obtained from formalin-fixed, paraffin-embedded preserved tissues. Results.--Our analysis identified, for the first time, expression of CCR4 in T-ALL/LBL in 11 of 27 cases (40.7%) and confirmed common expression of BCL2, CD38, and CD47, as reported previously. We also identified the expression of CD123 in 4 of 26 cases (15.4%), whereas BCL6 and PDL1 were expressed in a small number of T-ALL/LBL cases. The potential novel target CCR4 was significantly more common in the Pre/Pro-T immunophenotypic subtype, 6 of 9 (66.7%, P = .01). No additional differences in clinical and epidemiologic variables were noted among positive or negative CCR4 cases. Conclusions.--These findings support preclinical and clinical testing of therapies targeting CCR4, CD47, BCL2, CD38, and CD123 in T-ALL/LBL, and may help guide the development of targeted clinical trials in T-ALL/LBL, a rare disease in urgent need of novel therapies. [ABSTRACT FROM AUTHOR]

* Context.--Human epidermal growth factor (HER2/neu) gene amplification, a poor prognostic factor in invasive breast cancer, has shown substantial utility as a predictive marker, with significantly improved survival following anti-HER2 therapies like trastuzumab. Dual-color dual in situ hybridization (D-DISH), a recently introduced fully automated assay for HER2/neu evaluation on light microscopy, has several advantages over fluorescence in situ hybridization (FISH). Objective.--To standardize and validate the D-DISH assay using FISH as the gold standard and assess interobserver reproducibility in interpreting the D-DISH assay. Design.--D-DISH was performed using the latest HER2 Dual ISH DNA Probe Cocktail assay (Ventana Medical Systems Inc, Tucson, Arizona) in 148 cases of invasive breast cancer. The same block was used for performing immunohistochemistry by Ventana PATHWAY anti-HER2/neu (4B5) antibody and FISH assay by ZytoLight SPEC ERBB2/CEN17 Dual Color Probe. D-DISH was separately interpreted by 4 pathologists blinded to FISH results. Results.--Concordance of 98.65% and a Cohen κ value of 0.97 were observed between FISH and D-DISH. Intraclass correlation coefficient (0.93-0.97) and κ values (0.98-1.0) for interobserver reproducibility showed almost perfect agreement by D-DISH. Interobserver reproducibility was also evaluated for genomic heterogeneity, HER2 group categorization, and polysomy (κ values 0.42-0.74, 0.89-0.93, and 0.98-1.0, respectively). Conclusions.--We successfully validated the latest version of D-DISH assay as a substitute for FISH in predicting HER2 gene status with significant interobserver reproducibility, concluding that this D-DISH assay may be introduced in routine diagnostic services as a reflex test to ascertain HER2 gene status. [ABSTRACT FROM AUTHOR]

BACKGROUND: The American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011 or Z11) trial demonstrated no survival advantage with completion axillary lymph node dissection (ALND) for patients with T1-2 breast cancer, 1 to 2 positive SLNs who received adjuvant chemoradiation therapy. More than 70% of the cohort had estrogen receptor (ER)+ tumors. There is paucity of data on the adherence rate to Z11, as well as a dearth of data on the applicability of Z11 for the different subtypes. We conducted a large hospital-based study to evaluate the adherence rate to Z11 based on subtypes. STUDY DESIGN: The National Cancer Database was queried to evaluate 33,859 patients diagnosed with T1-2, N1, and M0 breast cancer treated with lumpectomy with negative margins, and adjuvant chemoradiation therapy between 2012 and 2018. Patients were classified into 3 groups: (1) ER+/HER2-, (2) ER-/HER2-, and (3) HER2+ regardless of ER status. The revised Scope of the Regional Lymph Node Surgery 2012 was used to classify patients into those who underwent an SLN or ALND. Differences in use of ALND by subtypes were compared. The Kaplan-Meier method and log-rank test were used to compare overall survival (OS). A p value of <0.05 was considered statistically significant. RESULTS: For ER+/human epidermal growth factor receptor 2 (HER2)-, ER-/HER2-, and HER2+ tumors, the rate of ALND was 43.6%, 50.2%, and 47.8%, respectively. The 5-year OS for SLN and ALND for the entire cohort was 94.0% and 93.1% (p = 0.0004); for ER+/HER2-, it was 95.4% and 94.7% (p = 0.04); for ER-/HER2-, it was 84.1% and 84.3% (p = 0.41); for HER2+, it was 94.2% and 93.2% (p = 0.20). Multivariable cox proportional hazard regression analysis demonstrated no significant survival differences between SLN and ALND (p = 0.776). CONCLUSIONS: Z11 is applicable for women with early N1 disease, regardless of subtypes. ALND did not confer a survival advantage over SLN. Despite this, up to 50% of patients who fit Z11 criteria continue to undergo ALND. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemotherapy (NCT) has become an increasingly popular approach in management of breast cancer (BC). This study was conducted to evaluate the pathologic response and 36-month recurrence and survival rates of patients with human epidermal growth factor receptor 2 (HER2)-negative BC treated with different NCT regimens. Methods: A total of 163 female patients with HER2-negative BC who received NCT during 2017-2020 were identified from the Clinical Breast Cancer Registry of Iran and entered the study. The prescribed NCT regimens included 4 cycles of doxorubicin plus cyclophosphamide, 4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of paclitaxel, 4 cycles of doxorubicin plus cyclophosphamide followed by 4 cycles of docetaxel or 6 cycles of doxorubicin plus cyclophosphamide plus docetaxel (TAC). Results: Thirty-two patients (19.6%) experienced pathologic complete response (pCR). TAC regimen, triple negative-BC and ki67 > 10% were significantly associated with increased pCR. The recurrence, overall survival (OS) and disease-free survival (DFS) rate at 36 months for all patients were 16.6%, 84.7% and 79.8%, respectively. Type of neoadjuvant regimen as well as age, hormone receptor status, Ki67, grade, clinical stage, type of surgery and pathologic response to chemotherapy did not significantly influence the survival and recurrence; however, TAC results in improved recurrence, OS and DFS rates. Conclusion: This study provides further evidence that NCT is a viable treatment option for patients with HER2-negative BC. The TAC regimen resulted in a significantly higher pCR rate compared to other regimens, but did not result in a significant improvement in recurrence, OS and DFS rates. [ABSTRACT FROM AUTHOR]

The aim of the study was to investigate the expression of EGFR and HER-2 oncogenes using an experimental two stage chemically induced carcinogenesis protocol on the dorsal skin in FVB/N mice. Forty female FVB/N mice 4 weeks old, were grouped into one control (n = 8) and two experimental groups (Group A: n = 16, Group B: n = 16) following a randomization process. Two-stage carcinogenesis protocol, was implicated, including an initial treatment with 97.4 nmol DMBA on their shaved dorsal skin and subsequent treatments of 32.4 nmol TPA applications after 13 weeks for Group A and after 20 weeks for Group B. The control group C, received no treatment. Skin was examined weekly for tumor development. Post-experiment, animals were euthanized for tissue analysis. The histological status of the skin lesions in the experimental groups corresponded well with tumour advancement (from dysplasia to poorly-differentiated carcinoma). Tumour sections were evaluated histologically and immunohistochemically. EGFR expression was found significantly higher in precancerous and malignant tumours (p = 042 and p = 008 respectively), while tended to be higher in benign tumours (p = 079), compared to normal histology. Moreover, mean percentage of EGFR positive expression in malignant tumours was significantly higher than in benign tumours (p < 001). HER-2 expression was found significantly higher in precancerous and malignant tumours (p = 042 and p = 015 respectively), while tended to be higher in benign tumours (p = 085), compared to normal histology. Furthermore, mean percentage of HER-2 positive expression in malignant tumours was significantly higher than in benign tumours (p = 005). The study demonstrated that in FVB/N mice subjected to a two-stage chemically induced carcinogenesis protocol, there was a significant increase in the expression of EGFR and HER-2 oncogenes in precancerous and malignant skin lesions compared to normal tissue. This suggests a potentially early role of these oncogenes in the progression of skin tumours in this model. [ABSTRACT FROM AUTHOR]

Objectives: The addition of CDK4/6 inhibitors to standard hormonotherapy improved progression-free survival(PFS) of hormone-positive, HER-2 negative metastatic breast cancer(mBC). We analyzed clinicopathological risk factors predicting early recurrence in mBC patients treated with a combination of CDK4/6 inhibitor and hormonotherapy. Methods: 229 patients were included, and 95 recurrences were seen. Median ER and PR expressions, ki67 levels, metastatic sites, number of metastasis, and grade were related to recurrence. Patients were classified according to the presence of prognostic factors: group 1 included patients with 0-1 risk factors, group 2 with 2-3 risk factors, and group 3 with ≥4risk factors. Results: Median ER, PR, and ki67 levels were 90, 60, and 25,respectively. Median ER, PR, Kİ67, grade, metastatic site, and the number of metastasis were related to PFS. Advanced CDK4/6 line and response were significant for PFS.Median PFS was 6.5 months for recurrent patients. According to the predictive model, patients who recurred before 6.5 months had a high-risk group (group 2,3). PS, family history, CDK4/6 inhibitor types were found to be related to PFS among the recurrent group. Conclusion: There is a need for a prospective design study to determine the clinicopathological markers identifying early recurrence under CDK4/6 inhibitors so new combination therapies or alternatives can be developed. [ABSTRACT FROM AUTHOR]

Targeting BRCA mutations with PARP inhibitors can increase progression-free survival in women with metastatic breast cancer who have these mutations. Unfortunately, this type of therapy has not yet been shown to improve survival. Using PARP inhibitors earlier in the disease process may significantly delay the time to recurrence. [ABSTRACT FROM AUTHOR]

Abnormal activation of the oncogene YAP in the Hippo pathway is a major feature in liver cancer and inactivation of MST1/2 has been shown to be responsible for the overactivation of YAP that led to tumorigenesis. However, mechanisms underlying MST1/2 dysregulation remain poorly understood. RNA‐seq analysis and genome (KEGG) pathway enrichment analysis were used to identify genes and pathways that were regulated by SIRT7. qRT‐PCR, ChIP, and luciferase assay were used to investigate transcriptional regulation. Mass spectrometry, co‐immunoprecipitation and immunoprecipitation were used to exam protein–protein interaction and post‐transcriptional modification. A xenograft mouse model was used to confirm the effect of SIRT7 and SIRT7 inhibitors on hepatocellular carcinoma (HCC) proliferation in vivo. We found that SIRT7 suppresses MST1 by both transcriptional regulation and post‐transcriptional modification, which in turn promotes YAP nuclear localization and transcriptional activation in liver cancer. Mechanistically, we revealed that SIRT7 suppresses MST1 transcription by binding to the MST1 promoter and inducing H3K18 deacetylation in its promoter region. In addition, SIRT7 directly binds to and deacetylates MST1, which primes acetylation‐dependent MST1 ubiquitination and protein degradation. In clinical samples, we confirmed a negative correlation between SIRT7 and MST1 protein levels, and high SIRT7 expression correlated with elevated YAP expression and nuclear localization. In addition, SIRT7 specific inhibitor 2800Z sufficiently inhibited HCC growth by disrupting the SIRT7/MST1/YAP axis. Our data thus revealed the previously undescribed function of SIRT7 in regulating the Hippo pathway in HCC and further proved that targeting SIRT7 might provide novel therapeutic options for the treatment of liver cancer. [ABSTRACT FROM AUTHOR]