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Organoid technology has been remarkably improved over the last decade. Various organoids have been derived from different types of tissues and recapitulate their organ-specific gene expression signatures, particular tissue spatial structures and functions of their original tissue. The patient-derived organoids (PDOs) have been used to elucidate crucial scientific questions, including the relationships between genetic/epigenetic alterations and drug responses, cell plasticity during disease progressions, and mechanisms of drug resistances. With the great expectations, PDOs will be widely used to facilitate the personalized medical decisions, which have the potential to profoundly improve patient outcomes. In this review, we will discuss the developmental details, current achievements, applications and challenges of organoid technology in precision cancer medicine. [ABSTRACT FROM AUTHOR]

Uncontrolled excessive activation of Hedgehog (Hh) signaling pathway is linked to a number of human malignant tumorigenesis. To obtain valuable Hh pathway inhibitors from natural product, in present study, a pair of novel epimers, Cynanbungeigenin C (CBC) and D (CBD) from the plant Cynanchum bungei Decne were chemically characterized by multiple spectroscopic data and chemical derivatization, and evaluated for their inhibition on Hh pathway. Mechanistically, CBC and CBD block Hh pathway signaling not through targeting Smo and Sufu, but at the level of Gli. In addition, both eipmers significantly suppress Hh pathway-dependent Ptch+/-; p53-/- medulloblastoma in vitro and in vivo. Furthermore, both CBC and CBD inhibited two Smo mutants induced Hh pathway activation, which suggested that they are potential compounds for the treatment of medulloblastoma with primary or acquired resistance to current Smo inhibitors. These results highlight the potential of CBC and CBD as effective lead compounds in the treatment of medulloblastoma and other Hh-dependent malignancy. [ABSTRACT FROM AUTHOR]

Neoadjuvant immunotherapy represents promising strategy in the treatment of esophageal squamous cell carcinoma (ESCC). However, the mechanisms underlying its impact on treatment sensitivity or resistance remain a subject of controversy. In this study, we conducted single-cell RNA and T/B cell receptor (scTCR/scBCR) sequencing of CD45+ immune cells on samples from 10 patients who received neoadjuvant immunotherapy and chemotherapy. We also validated our findings using multiplexed immunofluorescence and analyzed bulk RNA-seq from other cohorts in public database. By integrating analysis of 87357 CD45+ cells, we found GZMK + effector memory T cells (Tem) were relatively enriched and CXCL13+ exhausted T cells (Tex) and regulator T cells (Treg) decreased among responders, indicating a persistent anti-tumor memory process. Additionally, the enhanced presence of BCR expansion and somatic hypermutation process within TNFRSF13B + memory B cells (Bmem) suggested their roles in antigen presentation. This was further corroborated by the evidence of the T-B co-stimulation pattern and CXCL13-CXCR5 axis. The complexity of myeloid cell heterogeneity was also particularly pronounced. The elevated expression of S100A7 in ESCC, as detected by bulk RNA-seq, was associated with an exhausted and immunosuppressive tumor microenvironment. In summary, this study has unveiled a potential regulatory network among immune cells and the clonal dynamics of their functions, and the mechanisms of exhaustion and memory conversion between GZMK + Tem and TNFRSF13B + Bmem from antigen presentation and co-stimulation perspectives during neoadjuvant PD-1 blockade treatment in ESCC. • By integrating analysis of 87357 CD45+ cells, we defined CD8+ CXCL13+ exhausted T cells (Tex) were enriched and clonal expanded in the non-responsive patients and CD4+ LAIR2+Treg were in activated states and highly plastic with various clonal sharing, which pointed out an exhausted and immunosuppressive environment in non-responsive patient following PD-1 blockade treatment. While, GZMK + effector memory T cells (Tem) were relatively enriched in responders, which suggested a memory lasting anti-tumor process with the stem-like ab + and FCRL4+ memory B (Bmem) with more differentiated states and the BCR expansion phenomenon were observed in responders. The class-switch recombination (CSR) and somatic hypermutation (SHM) process were also enriched in TNFRSF13B + Bmem implying its mature state as antigen-presenting (APC) roles. Furthermore, T-B crosstalk process via CD28 − CD86 co-stimulation pattern and CXCL13-CXCR5 chemokines axis was validated using cellphoneDB algorithm and multiplex immunofluorescence (mIF) method. We also extracted a TNFRSF13B signature to predict response and OS benefits to immune checkpoint blockade in different cohorts to underscore their clinical relevance. • And the heterogeneity of myeloid cells was quite complex. According to pan-cancer results, we also validated FOLR2+ tissue-resident macrophage in our cohort showed a correlation with increment of Tem clusters, suggesting its APC roles. On the contrary, CCL3L1+ Neutrophils tended to a pro-tumoral phenotype with immunosuppressive and neutrophil extracellular traps (NETs) features. • While the elevated S100A7 in our ESCC cohort revealed by bulk RNA-seq relating to an exhaustion and immunosuppressive TME in upstream pathway may explain the inherent ICB resistance mechanism. [ABSTRACT FROM AUTHOR]

Abstract: In this study, we investigated the expression and function of thymosinα1 (Thyα1) in human pancreatic cancer. We found that human pancreatic cancer cell lines Panc-1, Panc03.27, ASPC-1, and PL45 cells significantly over-expressed the mRNA of Thyα1 as compared to the normal human pancreatic ductal epithelium (HPDE) cells.. Thyα1 mRNA and protein levels were also over-expressed in clinical pancreatic adenocarcinoma specimens. In addition, synthetic Thyα1 significantly promoted Panc-1 cell proliferation and increased phosphorylation of ERK1/2 and JNK. Furthermore, Thyα1 increased the secretion of multiple cytokines including IL-10, IL-13, and IL-17 in Panc-1 cells. Thus, Thyα1 may have a new role in pancreatic cancer pathogenesis. [Copyright &y& Elsevier]

Pancreatic cancer (PC), one of the most lethal malignancies, accounts for 8%-10% of digestive system cancers, and the incidence is increasing. Surgery, chemotherapy, and radiotherapy have been the main treatment methods but are not very effective. However, only 20% of patients have the opportunity to undergo surgical operation. Approximately 30-40% of patients present with locally advanced, unresectable pancreatic cancer because of invasion of mesenteric vessels or adjacent organs. The first patient with unresectable pancreatic cancer was treated with Intraoperative radiotherapy (IORT) in 1959 [1]. Since then, new surgical and radiotherapeutic techniques have been developed, clinical trials have provided new evidence, and intriguing long-term effects have emerged from global metadatabases. IORT has the advantages of more accurate target, better local control rate, less complications, longer survival time and better life quality. During the past decade, IORT has been applied in some hospitals in the world, but there is little agreement on technical details and standards. A guidelines of IORT in pancreatic cancer is therefore necessary and timely. To develop standardized criteria for the application of IORT in pancreatic cancer, the experts from China to discuss treatment methods and arrive at a consensus on the indications, contraindications, and preferred techniques of IORT in pancreatic cancer. This detailed and agreed technical description of IORT may have implications on training, assessment, quality control, and future research. [ABSTRACT FROM AUTHOR]

The roles of miRNAs in the development of cancer have made them promising tools for novel therapeutic approaches. However, the successful delivery of miRNAs to cancer cells has been hampered by difficulties in developing an effective and sustainable delivery mechanism. Exosomes are small endogenous membrane vesicles that mediate communication between cells by delivering genetic materials. Thus, given their intrinsic properties, exosomes have been a focus for use as biological delivery vehicles for miRNAs transfer. Whether exosomes can effectively deliver exogenous miRNAs to pancreatic ductal adenocarcinoma (PDAC) cells has not been thoroughly investigated. Here, we used exosomes from human umbilical cord mesenchymal stromal cells (hucMSCs) to deliver exogenous miR-145-5p, which inhibited PDAC cell proliferation and invasion and increased apoptosis and cell cycle arrest, concomitant with decreased Smad3 expression in vitro. Using a mouse model, we also demonstrated that overexpressing miR-145-5p significantly reduced the growth of xenograft tumors in vivo. Our findings provide novel insights that exosomes might be an attractive therapeutic vehicle for the clinical administration of miRNAs in patients with PDAC. [ABSTRACT FROM AUTHOR]

Introduction of bortezomib, the first generation of proteasome inhibitor, has significantly improved the median overall survival of patients with multiple myeloma (MM). However, the dose-limiting adverse events and acquired drug resistance limit its long-term usage. Here, we report in vitro and in vivo anti-MM activity of the irreversible proteasome inhibitor BSc2118. BSc2118 inhibited the chymotrypsin-like (CT-L) proteasome activity, accompanied by accumulation of ubiquitinated proteins. BSc2118 suppressed tumor cell growth through induction of G2/M phase arrest and induced apoptosis via activation of the apoptotic signaling cascade, in association with up-regulation of p53 and p21. Importantly, BSc2118 was active in vitro against MM cells' acquired bortezomib resistance. Of note, BSc2118 also displayed a novel anti-angiogenesis activity both in vitro and in vivo . Lastly, BSc2118 exhibited a broader safety dose range and higher anti-tumor efficacy in vivo in a human MM xenograft mouse model, compared to bortezomib. Together, these findings indicate the in vitro and in vivo anti-MM activities of BSc2118 through induction of cell cycle arrest and apoptosis, as well as inhibition of tumor angiogenesis. They also suggest that BSc2118 might, at least in vitro , partially overcome acquired bortezomib resistance, likely associated with inhibition of autophagy. [ABSTRACT FROM AUTHOR]

Abstract: The aim of the present study was to investigate the role of Stat3 in cisplatin resistant ovarian cancer. It was first demonstrated that higher activated Stat3 was detected in cisplatin-resistant ovarian cancer cell lines. To provide evidence that supported the hypothesis that phosphorylated-Stat3 expression may promote cisplatin resistance, ectopic Stat3 was expressed by IL-6 stimulation that partially abrogates Stat3, as opposed to the knock-down of Stat3 by specific siRNA that restores cisplatin sensitivity against ovarian cancer cells. This hypothesis was further confirmed by clinical tumor specimens of ovarian cancer obtained from patients with cisplatin-resistance. Based on these premises, Stattic [1], an effective small molecular inhibitor of Stat3, was used to inhibit Stat3 activation. The data presented here show that Stattic restored the sensitivity to cisplatin in chemoresistant ovarian cancer by significant reductions in the expression of the anti-apoptosis protein Bcl-2, Bcl-XL, Survivin protein and phosphorylated-Akt levels. Consistent with these observations, this experiment demonstrated the first evidence of Stattic circumvented cisplatin resistance of orthotopic xenograft ovarian cancer in vivo. Altogether, these findings emphasize the importance of Stat3 in cisplatin resistance in ovarian cancer and provide a further impetus to clinically evaluate biological modifiers that may circumvent cisplatin resistance in patients with chemoresistant ovarian cancer. [Copyright &y& Elsevier]

Abstract: Caveolin-1, a 21–24kDa integral membrane protein, is a principal structural component of caveolae in vivo. To investigate the roles of caveolin-1, we established stable transfectants in Hs578T breast adenocarcinoma cells that had up- and down-regulated caveolin-1 expression. In the paper, we demonstrated that caveolin-1 overexpression in Hs578T cells significantly reduced staurosporine-induced apoptosis and the levels of caveolin-1 expression positively correlated with the number of colonies and colony size in soft agar. Our findings indicate for the first time in Hs578T cells that caveolin-1 might play a pivotal role in regulating apoptosis as a suppressor rather than a facilitator through inhibition of neutral-sphingomyelinase, decrease of ceramide, furthermore, activation of Akt signaling pathway. [Copyright &y& Elsevier]