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The TP63 is an indispensable transcription factor for development and homeostasis of epithelia and its derived glandular tissue. It is also involved in female germline cell quality control, muscle and thymus development. It is expressed as multiple isoforms transcribed by two independent promoters, in addition to alternative splicing occurring at the mRNA 3′-UTR. Expression of the TP63 gene, specifically the amino-deleted p63 isoform, ΔNp63, is required to regulate numerous biological activities, including lineage specification, self-renewal capacity of epithelial stem cells, proliferation/expansion of basal keratinocytes, differentiation of stratified epithelia. In cancer, ΔNp63 is implicated in squamous cancers pathogenesis of different origin including skin, head and neck and lung and in sustaining self-renewal of cancer stem cells. How this transcription factor can control such a diverse set of biological pathways is central to the understanding of the molecular mechanisms through which p63 acquires oncogenic activity, profoundly changing its down-stream transcriptional signature. Here, we highlight how different proteins interacting with p63 allow it to regulate the transcription of several central genes. The interacting proteins include transcription factors/regulators, epigenetic modifiers, and post-transcriptional modifiers. Moreover, as p63 depends on its interactome, we discuss the hypothesis to target the protein interactors to directly affect p63 oncogenic activities and p63-related diseases.

The transcription factor p63, belonging to the p53 family, is considered the master regulator of epidermal differentiation, skin, and in general of the differentiation of ectodermal tissues. Mutations in TP63 gene cause several rare ectodermal dysplasia disorders that refers to epidermal structural abnormalities and ocular surface disease, such as Ectrodactyly Ectodermal Dysplasia Clefting (EEC) syndrome. In this review, we discuss the key roles of p63 in keratinocytes and corneal epithelial differentiation, highlighting the function of the ΔNp63α isoform in driving limbal stem cell and epithelial stem cells commitment. We have summarized the specific ocular phenotypes observed in the TP63-mutation derived EEC syndrome, discussing the current and novel therapeutic strategies for the management of the ocular manifestations in EEC syndrome.

R-loops are inherent byproducts of transcription consisting of an RNA:DNA hybrid and a displaced single-stranded DNA. These structures are of key importance in controlling numerous physiological processes and their homeostasis is tightly controlled by the activities of several enzymes deputed to process R-loops and prevent their unproper accumulation. Senataxin (SETX) is an RNA/DNA helicase which catalyzes the unwinding of RNA:DNA hybrid portion of the R-loops, promoting thus their resolution. The key importance of SETX in R-loops homeostasis and its relevance with pathophysiological events is highlighted by the evidence that gain or loss of function SETX mutations underlie the pathogenesis of two distinct neurological disorders. Here, we aim to describe the potential impact of SETX on tumor onset and progression, trying to emphasize how dysregulation of this enzyme observed in human tumors might impact tumorigenesis. To this aim, we will describe the functional relevance of SETX in regulating gene expression, genome integrity, and inflammation response and discuss how cancer-associated SETX mutations might affect these pathways, contributing thus to tumor development.

An essential function of the epidermis is to provide a physical barrier that prevents the loss of water. Essential mediators of this barrier function include ceramides, cholesterol, and very long chain fatty acids, and their alteration causes human pathologies, including psoriasis and atopic dermatitis. A frameshift mutation in the human ZNF750 gene, which encodes a zinc finger transcription factor, has been shown to cause a seborrhea-like dermatitis. Here, we show that genetic deletion of the mouse homolog ZFP750 results in loss of epidermal barrier function, which is associated with a substantial reduction of ceramides, nonpolar lipids. The alteration of epidermal lipid homeostasis is directly linked to the transcriptional activity of ZFP750. ZFP750 directly and/or indirectly regulates the expression of crucial enzymes primarily involved in the biosynthesis of ceramides. Overall, our study identifies the transcription factor ZFP750 as a master regulator epidermal homeostasis through lipid biosynthesis and thus contributing to our understanding of the pathogenesis of several human skin diseases.

Supplementary Figure 2 from Netrin-1 Induces Apoptosis in Human Cervical Tumor Cells via the TAp73α Tumor Suppressor

Supplementary Figure 1 from Netrin-1 Induces Apoptosis in Human Cervical Tumor Cells via the TAp73α Tumor Suppressor

Prostate cancer is the most frequently diagnosed cancer and the fifth leading cause of cancer death among men in 2020. The clinical decision making for prostate cancer patients is based on the stratification of the patients according to both clinical and pathological parameters such as Gleason score and prostate-specific antigen levels. However, these tools still do not adequately predict patient outcome. The aim of this study was to investigate whether ZNF750 could have a role in better stratifying patients, identifying those with a higher risk of metastasis and with the poorest prognosis. The data reported here revealed that ZNF750 protein levels are reduced in human prostate cancer samples, and this reduction is even higher in metastatic samples. Interestingly, nuclear positivity is significantly reduced in patients with metastatic prostate cancer, regardless of both Gleason score and grade group. More importantly, the bioinformatics analysis indicates that ZNF750 expression is positively correlated with better prognosis. Overall, our findings suggest that nuclear expression of ZNF750 may be a reliable prognostic biomarker for metastatic prostate cancer, which lays the foundation for the development of new biological therapies.

Supplementary Methods, Figures 1-4 from Negative Regulation of the Hippo Pathway by E3 Ubiquitin Ligase ITCH Is Sufficient to Promote Tumorigenicity

Recent development of human three-dimensional organoid cultures has opened new doors and opportunities ranging from modelling human development in vitro to personalised cancer therapies. These new in vitro systems are opening new horizons to the classic understanding of human development and disease. However, the complexity and heterogeneity of these models requires cutting-edge techniques to capture and trace global changes in gene expression to enable identification of key players and uncover the underlying molecular mechanisms. Rapid development of sequencing approaches made possible global transcriptome analyses and epigenetic profiling. Despite challenges in organoid culture and handling, these techniques are now being adapted to embrace organoids derived from a wide range of human tissues. Here, we review current state-of-the-art multi-omics technologies, such as single-cell transcriptomics and chromatin accessibility assays, employed to study organoids as a model for development and a platform for precision medicine.

Non-melanoma skin cancer (NMSC) is a tumor that arises from human keratinocytes, showing abnormal control of cell proliferation and aberrant stratification. Cutaneous basal cell carcinoma (cBCC) and cutaneous squamous cell carcinoma (cSCC) are the most common sub-types of NMSC. From a molecular point of view, we are still far from fully understanding the molecular mechanisms behind the onset and progression of NMSC and to unravel targetable vulnerabilities to leverage for their treatment, which is still essentially based on surgery. Under this assumption, it is still not elucidated how the central cellular metabolism, a potential therapeutical target, is involved in NMSC progression. Therefore, our work is based on the characterization of the serine anabolism/catabolism and/or one-carbon metabolism (OCM) role in NMSC pathogenesis. Expression and protein analysis of normal skin and NMSC samples show the alteration of the expression of two enzymes involved in the serine metabolism and OCM, the Serine Hydroxy-Methyl Transferase 2 (SHMT2) and Methylen-ThetraHydroFolate dehydrogenase/cyclohydrolase 2 (MTHFD2). Tissues analysis shows that these two enzymes are mainly expressed in the proliferative areas of cBCC and in the poorly differentiated areas of cSCC, suggesting their role in tumor proliferation maintenance. Moreover, in vitro silencing of SHMT2 and MTHFD2 impairs the proliferation of epidermoid cancer cell line. Taken together these data allow us to link the central cellular metabolism (serine and/or OCM) and NMSC proliferation and progression, offering the opportunity to modulate pharmacologically the involved enzymes activity against this type of human cancer.

Dysregulated mitochondrial fusion and fission has been implicated in the pathogenesis of numerous diseases. We have identified a novel function of the p53 family protein TAp73 in regulating mitochondrial dynamics. TAp73 regulates the expression of Optic atrophy 1, a protein responsible for controlling mitochondrial fusion, cristae biogenesis and electron transport chain function. Disruption of this axis results in a fragmented mitochondrial network and an impaired capacity for energy productionviaoxidative phosphorylation. Owing to the role of OPA1 in modulating cytochromecrelease, TAp73-/-cells also display an increased sensitivity to apoptotic cell death, e.g.,viaBH3-mimetics. We also show that the TAp73/OPA1 axis has functional relevance in the upper airway, where TAp73 expression is essential for multiciliated cell differentiation and function. Consistently, ciliated epithelial cells ofTrp73-/-(global p73 KO) mice display decreased expression of OPA1 and perturbations of the mitochondrial network, which may drive multiciliated cell loss. In support of this,Trp73andOPA1gene expression is decreased in COPD patients, a disease characterised by alterations in mitochondrial dynamics. We therefore highlight a potential mechanism involving the loss of p73 in COPD pathogenesis. This work also adds to the growing body of evidence for growth-promoting roles of TAp73 isoforms.

Nuclear organisation and architecture are essential for the maintenance of genomic integrity as well as for the epigenetic regulations and gene expression. Disruption of lamin B1, major structural and functional member of the nuclear lamina, is observed in human laminopathies and in sporadic cancers, and leads to chromosomal rearrangements and alterations of gene expression. The tumour suppressor p53 has been shown to direct specific transcriptional programmes by regulating lamin A/C, however its relationship with lamin B1 has remained elusive. Here, we show that loss of p53 correlates with increased expression of members belonging to the nuclear pore complex and nuclear lamina and directly regulates transcription of lamin B1. We show that the genomic loci of a fraction of p53-dependent genes physically interact with lamin B1 and Nup210. This observation provides a possible mechanistic explanation for the p53-depedent changes of chromatin accessibility, with the consequent influence of expression and rearrangement of these genomic sites in pancreatic cancer. Overall, these data suggest a potential functional and biochemical regulatory network connecting p53 and nuclear architecture.

The transcription factor p53 has been shown to control the differentiation process of the mesenchymal stem cells (MSCs). As a matter of fact, in vivo p53 loss leads to an unbalance between bone formation versus bone erosion. Using as experimental system, human bone marrow-derived MSCs and mouse bone marrow-derived TAp63-/- MSCs, we have asked whether the other members of the p53 family, p63 and p73, are involved in controlling MSCs osteogenic differentiation. Our results indicate that both during human and mouse MSC-induced osteogenic differentiation, TAp63 isoforms are mainly upregulated in comparison with p73 isoforms. In addition, MSCs derived from TAp63 knock-out mice show delayed osteogenic differentiation. Interestingly, we found that, in contrast to p53, TAp63 trascriptionally regulates osteoprotegerin (OPG or TNFRSF11B) important for bone remodeling and osteoclastogenesis inhibition throughout the RANKL/RANK/OPG pathway. Analysis of the expression of p63 and OPG in breast cancer, which is one of the most common human cancers that metastatizes to bone, showed that p63/OPG pathway is deregulated and that a higher expression of both p63 and OPG is associated with a better patient survival, suggesting that p63/OPG axis may be further investigated as clinical biomarker for breast cancer metastasis. ABBREVIATIONS: MSC, mesenchymal stem cells; OPG, osteoprotegerin; RUNX2, Run-trelated transcription factor 2

Gene-environment interactions can perturb the epigenome, triggering network alterations that participate in cancer pathogenesis. Integrating epigenomics, transcriptomics, and metabolic analyses with functional perturbation, we show that the tumor suppressor p53 preserves genomic integrity by empowering adequate levels of the universal methyl donor S-adenosylmethionine (SAM). In p53-deficient cells, perturbation of DNA methylation promotes derepression of heterochromatin, massive loss of histone H3-lysine 9 methylation, and consequent upregulation of satellite RNAs that triggers R-loop-associated replication stress and chromosomal aberrations. In p53-deficient cells, the inadequate SAM level underlies the inability to respond to perturbation because exogenous reintroduction of SAM represses satellite elements and restores the ability to cope with stress. Mechanistically, p53 transcriptionally controls genes involved in one-carbon metabolism, including Slc43a2, the methionine uptake transporter that is critical for SAM synthesis. Supported by clinical data, our findings shed light on the role of p53-mediated metabolism in preventing unscheduled R-loop-associated genomic instability. published

Although targeting cancer metabolism is a promising therapeutic strategy, clinical success depends on accurate molecular and metabolic subtyping. Here, this study reports two metabolism-based molecular subtypes associated with the ketogenic treatment of colon cancer: glycolytic (glycolysissup+/sup/ketolysissup-/sup) and ketolytic (glycolysissup+/sup/ketolysissup+/sup), which are manifested by distinct profiles of metabolic enzymes and mitochondrial dysfunction, and by different responses to ketone-containing interventions in vitro and in vivo. Notably, the glycolytic subtype is able to be transformed into the ketolytic subtype in p53-mutated tumors upon glucose limitation, rendering resistance to ketogenic therapy associated with upregulation of ketolytic enzymes, such as OXCT1 by mutant p53. The allosteric activator of mutant p53 effectively blocks the rewired molecular expression and the reprogrammed metabolism, leading to the suppression of tumor growth. The findings highlight the utility of metabolic subtyping to guide ketogenic therapy in colon cancer and identify mutant p53 as a synthetic lethality target for ketogenic treatment.

The use of immune checkpoint inhibitors (ICI) to activate adaptive immune responses against some tumor types has clearly been a major advance in cancer therapeutics1 . Despite the significant impact of ICI implementation on the outcomes of cancers, treatments with ICI currently fail to eradicate the majority of tumors as a result of inadequate priming of an autologous tumor-specific immune response. Three collaborative studies published by the groups of B. Vogelstein, S. B. Gabelli and S. Zhou indicate that specially-designed bispecific antibodies may help overcome limitations of ICI.

Distinct metabolic programs, either energy-consuming anabolism or energy-generating catabolism, were required for different biological functions. Macrophages can adopt different immune phenotypes in response to various cues and exhibit anti- or pro-inflammatory properties relying on catabolic pathways associated with oxidative phosphorylation (OXPHOS) or glycolysis. Spermidine, a natural polyamine, has been reported to regulate inflammation through inducing anti-inflammatory (M2) macrophages. However, the underlying mechanisms remain elusive. We show here that the M2-polarization induced by spermidine is mediated by mitochondrial reactive oxygen species (mtROS). The levels of mitochondrial superoxide and H2O2 were markedly elevated by spermidine. Mechanistically, mtROS were found to activate AMP-activated protein kinase (AMPK), which in turn enhanced mitochondrial function. Furthermore, hypoxia-inducible factor-1α (Hif-1α) was upregulated by the AMPK activation and mtROS and was required for the expression of anti-inflammatory genes and induction of autophagy. Consistent with previous report that autophagy is required for the M2 polarization, we found that the M2 polarization induced by spermidine was also mediated by increased autophagy. The macrophages treated with spermidine in vitro were found to ameliorate Dextran Sulfate Sodium (DSS)-induced inflammatory bowel disease (IBD) in mice. Thus, spermidine can elicit an anti-inflammatory program driven by mtROS-dependent AMPK activation, Hif-1α stabilization and autophagy induction in macrophages. Our studies revealed a critical role of mtROS in shaping macrophages into M2-like phenotype and provided novel information for management of inflammatory disease by spermidine.

Significance ΔNp63 is a master regulator of skin homeostasis since it finely controls keratinocyte differentiation and proliferation. Here, we provide cellular and molecular evidence demonstrating the functional role of a ΔNp63 interactor, the R-loop–resolving enzyme Senataxin (SETX), in fine-tuning keratinocyte differentiation. We found that SETX physically binds the p63 DNA–binding motif present in two early epidermal differentiation genes, Keratin 1 (KRT1) and ZNF750, facilitating R-loop removal over their 3′ ends and thus allowing efficient transcriptional termination and gene expression. These molecular events translate into the inability of SETX-depleted keratinocytes to undergo the correct epidermal differentiation program. Remarkably, SETX is dysregulated in cutaneous squamous cell carcinoma, suggesting its potential involvement in the pathogenesis of skin disorders.

Aetiogenesis of cancer has not been fully determined. Recent advances have clearly defined a role for microenvironmental factors in cancer progression and initiation; in this context, microbiome has recently emerged with a number of reported correlative and causative links implicating alterations of commensal microbes in tumorigenesis. Bacteria appear to have the potential to directly alter physiological pathways of host cells and in specific circumstances, such as the mutation of the tumour suppressive factor p53, they can also directly switch the function of a gene from oncosuppressive to oncogenic. In this minireview, we report a number of examples on how commensal microbes alter the host cell biology, affecting the oncogenic process. We then discuss more in detail how interaction with the gut microbiome can affect the function of p53 mutant in the intestinal tumorigenesis.

Over 20 years after identification of p53 and its crucial function in cancer progression, two members of the same protein family were identified, namely p63 and p73. Since then, a body of information has been accumulated on each of these genes and their interrelations. Biological role of p73 has been elucidated thanks to four distinct knockout mice models: (i) with deletion of the entire TP73 gene, (ii) with deletion of exons encoding the full length TAp73 isoforms, (iii) with deletions of exons encoding the shorter DNp73 isoform, and (iv) with deletion of exons encoding C-terminal of the alpha isoform. This work, as well as expression studies in cancer and overwhelming body of molecular studies, allowed establishing major role of TP73 both in cancer and in neuro-development, as well as ciliogenesis, and metabolism. Here, we recapitulate the major milestones of this endeavor.

Skin is the largest organ of the human body. Skin wound is one of the most common forms of wound. Mesenchymal stromal cells (MSCs) have been used to aid skin wound healing via their paracrine factors. Because the secretome of MSCs can be greatly enriched and amplified by treatment with IFN‐γ and TNF‐α (IT), we here tested whether supernatant derived from MSCs pretreated with IT, designated as S‐MSCs‐IT, possesses improved wound healing effect by using a murine model of cutaneous excision, S‐MSCs‐IT was found to be more potent in promoting angiogenesis, constricting collagen deposition and accelerating wound closure than control supernatant (S‐MSCs) during the healing of skin wound. VEGFC, but not VEGFA, was greatly upregulated by IT and was found to be a key factor in mediating the improved wound healing effect of S‐MSCs‐IT. Our results indicate that the beneficial paracrine effect of MSCs on wound healing can be enhanced by pretreatment with inflammatory cytokines. IT treatment may represent a new strategy for optimizing the therapeutic effect of MSCs on skin injuries., TNF‐α and IFN‐γ stimulation upregulates the expression of VEGFC in mesenchymal stromal cells, which acts on endothelial cells and promotes angiogenesis, thus accelerating skin wound healing.

Cytokines produced by immune cells have been demonstrated to act on muscle stem cells (MuSCs) and direct their fate and behavior during muscle repair and regeneration. Nevertheless, it is unclear whether and how MuSCs can also in turn modulate the properties of immune cells. Here, we showed that in vitro expanded MuSCs exhibited a potent anti‐inflammatory effect when infused into mice suffering from inflammatory bowel disease (IBD). Supernatant conditioned by MuSCs similarly ameliorated IBD. This beneficial effect of MuSCs was not observed when macrophages were depleted. The MuSC supernatant was found to greatly attenuate the expression of inflammatory cytokines but increase the expression of programmed death‐ligand 1 in macrophages treated with lipopolysaccharide and interferon gamma. Further analysis revealed that MuSCs produce a large amount of insulin‐like growth factor‐2 (IGF‐2) that instructs maturing macrophages to undergo oxidative phosphorylation and thus acquire anti‐inflammatory properties. Interestingly, the IGF‐2 production by MuSCs is much higher than by mesenchymal stem cells. Knockdown or neutralization of IGF‐2 abrogated the anti‐inflammatory effects of MuSCs and their therapeutic efficacy on IBD. Our study demonstrated that MuSCs possess a strong anti‐inflammatory property and the bidirectional interactions between immune cells and MuSCs have important implications in muscle‐related physiological and pathological conditions., Immune cells are known to direct the fate of muscle stem cells (MuSCs) during tissue repair and regeneration. MuSCs can also act on maturing macrophages and confer them with anti‐inflammatory properties via insulin‐like growth factor‐2, thus ameliorating dextran sulfate sodium‐induced colitis.

The p53 family transcriptional factor p73 plays a pivotal role in development. Ablation of p73 results in severe neurodevelopmental defects, chronic infections, inflammation and infertility. In addition to this, Trp73(−\-) mice display severe alteration in the ciliated epithelial lining and the full-length N-terminal isoform TAp73 has been implicated in the control of multiciliogenesis transcriptional program. With our recently generated Trp73(Δ13/Δ13) mouse model, we interrogate the physiological role of p73 C-terminal isoforms in vivo. Trp73(Δ13/Δ13) mice lack exon 13 in Trp73 gene, producing an ectopic switch from the C-terminal isoforms p73α to p73β. Trp73(Δ13/Δ13) mice show a pattern of expression of TAp73 comparable to the wild-type littermates, indicating that the α to β switch does not significantly alter the expression of the gene in this cell type. Moreover, Trp73(Δ13/Δ13) do not display any significant alteration in the airway ciliated epithelium, suggesting that in this context p73β can fully substitute the function of the longer isoform p73α. Similarly, Trp73(Δ13/Δ13) ciliated epithelium of the brain ependyma also does appear defective. In this district however expression of TAp73 is not detectable, indicating that expression of the gene might be compensated by alternative mechanisms. Overall our work indicates that C-terminus p73 is dispensable for the multiciliogenesis program and suggests a possible tissue-specific effect of p73 alternative splicing.

Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265, Funder: Fondazione Luigi Maria Monti IDI-IRCCS (RC), Regulatory noncoding RNAs (ncRNAs) are a class of RNAs transcribed by regions of the human genome that do not encode for proteins. The three main members of this class, named microRNA, long noncoding RNA, and circular RNA play a key role in the regulation of gene expression, eventually shaping critical cellular processes. Compelling experimental evidence shows that ncRNAs function either as tumor suppressors or oncogenes by participating in the regulation of one or several cancer hallmarks, including evading cell death, and their expression is frequently deregulated during cancer onset, progression, and dissemination. More recently, preclinical and clinical studies indicate that ncRNAs are potential biomarkers for monitoring cancer progression, relapse, and response to cancer therapy. Here, we will discuss the role of noncoding RNAs in regulating cancer cell death, focusing on those ncRNAs with a potential clinical relevance.

Adaptation of the lipid metabolism participates in cancer pathogenesis, facilitating energy storage and influencing cell fate and control of molecular signalling. The tumour suppressor protein p53 is a molecular hub of cell metabolism, supporting antioxidant capabilities and counteracting oncogene-induced metabolic switch. Despite extensive work has described the p53-dependent metabolic pathways, a global profiling of p53 lipidome is still missing. By high-throughput untargeted lipidomic analysis of pancreatic ductal adenocarcinoma (PDAC) cells, we profile the p53-dependent lipidome, revealing intracellular and secreted lysophospholipids as one of the most affected class. Lysophospholipids are hydrolysed forms of phospholipids that results from phospholipase activity, which can function as signalling molecules, exerting non-cell-autonomous effects and instructing cancer microenvironment and immunity. Here, we reveal that p53 depletion reduces abundance of intracellular lysophosphatidyl-choline, -ethanolamine and -serine and their secretion in the extracellular environment. By integrating this with genomic and transcriptomic studies from in vitro models and human PDAC patients, we identified potential clinically relevant candidate p53-dependent phospholipases. In particular PLD3, PLCB4 and PLCD4 expression is regulated by p53 and chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) indicates a direct transcriptional control on their chromatin accessible genomic loci. Consistently, PLD3, PLCB4 and PLCD4 expression correlates with p53 mutational status in PDAC patients, and these genes display prognostic significance. Overall, our data provide insights into lipidome rewiring driven by p53 loss and identify alterations of lysophospholipids as a potential molecular mechanism for p53-mediated non-cell-autonomous molecular signalling that instructs cancer microenvironment and immunity during PDAC pathogenesis.

Senescence is believed to be a pivotal player in the onset and progression of tumors as well as cancer therapy. However, the guiding roles of senescence in clinical outcomes and therapy selection for patients with cancer remain obscure, largely due to the absence of a feasible senescence signature. Here, by integrative analysis of single cell and bulk transcriptome data from multiple datasets of gastric cancer patients, we uncovered senescence as a veiled tumor feature characterized by senescence gene signature enriched, unexpectedly, in the noncancerous cells, and further identified two distinct senescence-associated subtypes based on the unsupervised clustering. Patients with the senescence subtype had higher tumor mutation loads and better prognosis as compared with the aggressive subtype. By the machine learning, we constructed a scoring system termed as senescore based on six signature genes: ADH1B, IL1A, SERPINE1, SPARC, EZH2, and TNFAIP2. Higher senescore demonstrated robustly predictive capability for longer overall and recurrence-free survival in 2290 gastric cancer samples, which was independently validated by the multiplex staining analysis of gastric cancer samples on the tissue microarray. Remarkably, the senescore signature served as a reliable predictor of chemotherapeutic and immunotherapeutic efficacies, with high-senescore patients benefited from immunotherapy, while low-senescore patients were responsive to chemotherapy. Collectively, we report senescence as a heretofore unrecognized hallmark of gastric cancer that impacts patient outcomes and therapeutic efficacy.

The understanding of the pathogenesis of renal cell carcinoma led to the development of targeted therapies, which dramatically changed the overall survival rate. Nonetheless, despite innovative lines of therapy accessible to patients, the prognosis remains severe in most cases. Kidney cancer rarely shows mutations in the genes coding for proteins involved in programmed cell death, including p53. In this paper, we show that the molecular machinery responsible for different forms of cell death, such as apoptosis, ferroptosis, pyroptosis, and necroptosis, which are somehow impaired in kidney cancer to allow cancer cell growth and development, was reactivated by targeted pharmacological intervention. The aim of the present review was to summarize the modality of programmed cell death in the pathogenesis of renal cell carcinoma, showing in vitro and in vivo evidence of their potential role in controlling kidney cancer growth, and highlighting their possible therapeutic value.

The coronavirus disease 2019 (COVID-19) has been a global pandemic for more than 2 years and it still impacts our daily lifestyle and quality in unprecedented ways. A better understanding of immunity and its regulation in response to SARS-CoV-2 infection is urgently needed. Based on the current literature, we review here the various virus mutations and the evolving disease manifestations along with the alterations of immune responses with specific focuses on the innate immune response, neutrophil extracellular traps, humoral immunity, and cellular immunity. Different types of vaccines were compared and analyzed based on their unique properties to elicit specific immunity. Various therapeutic strategies such as antibody, anti-viral medications and inflammation control were discussed. We predict that with the available and continuously emerging new technologies, more powerful vaccines and administration schedules, more effective medications and better public health measures, the COVID-19 pandemic will be under control in the near future.

Penetration of immune cells into tumor cells was believed to be immune-suppressive via cell-in-cell (CIC) mediated death of the internalized immune cells. We unexpectedly found that CIC formation largely led to the death of the host tumor cells, but not the internalized immune cells, manifesting typical features of death executed by NK cells; we named this “in-cell killing” which displays the efficacy superior to the canonical way of “kiss-killing” from outside. By profiling isogenic cells, CD44 on tumor cells was identified as a negative regulator of “in-cell killing” via inhibiting CIC formation. CD44 functions to antagonize NK cell internalization by reducing N-cadherin-mediated intercellular adhesion and by enhancing Rho GTPase-regulated cellular stiffness as well. Remarkably, antibody-mediated blockade of CD44 signaling potentiated the suppressive effects of NK cells on tumor growth associated with increased heterotypic CIC formation. Together, we identified CIC-mediated “in-cell killing” as a promising strategy for cancer immunotherapy.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is highly contagious and causes lymphocytopenia, but the underlying mechanisms are poorly understood. We demonstrate here that heterotypic cell-in-cell structures with lymphocytes inside multinucleate syncytia are prevalent in the lung tissues of coronavirus disease 2019 (COVID-19) patients. These unique cellular structures are a direct result of SARS-CoV-2 infection, as the expression of the SARS-CoV-2 spike glycoprotein is sufficient to induce a rapid (approximately 45.1 nm/sec) membrane fusion to produce syncytium, which could readily internalize multiple lines of lymphocytes to form typical cell-in-cell structures, remarkably leading to the death of internalized cells. This membrane fusion is dictated by a bi-arginine motif within the polybasic S1/S2 cleavage site, which is frequently present in the surface glycoprotein of most highly contagious viruses. Moreover, candidate anti-viral drugs could efficiently inhibit spike glycoprotein processing, membrane fusion, and cell-in-cell formation. Together, we delineate a molecular and cellular rationale for SARS-CoV-2 pathogenesis and identify novel targets for COVID-19 therapy.

During oncogenesis, cells become unrestrictedly proliferative thereby altering the tissue homeostasis and resulting in subsequent hyperplasia. This process is paralleled by resumption of cell cycle, aberrant DNA repair and blunting the apoptotic program in response to DNA damage. In most human cancers these processes are associated with malfunctioning of tumor suppressor p53. Intriguingly, in some cases two other members of the p53 family of proteins, transcription factors p63 and p73, can compensate for loss of p53. Although both p63 and p73 can bind the same DNA sequences as p53 and their transcriptionally active isoforms are able to regulate the expression of p53-dependent genes, the strongest overlap with p53 functions was detected for p73. Surprisingly, unlike p53, the p73 is rarely lost or mutated in cancers. On the contrary, its inactive isoforms are often overexpressed in cancer. In this review, we discuss several lines of evidence that cancer cells develop various mechanisms to repress p73-mediated cell death. Moreover, p73 isoforms may promote cancer growth by enhancing an anti-oxidative response, the Warburg effect and by repressing senescence. Thus, we speculate that the role of p73 in tumorigenesis can be ambivalent and hence, requires new therapeutic strategies that would specifically repress the oncogenic functions of p73, while keeping its tumor suppressive properties intact.

Skeletal muscle has an extraordinary regenerative capacity reflecting the rapid activation and effective differentiation of muscle stem cells (MuSCs). In the course of muscle regeneration, MuSCs are reprogrammed by immune cells. In turn, MuSCs confer immune cells anti-inflammatory properties to resolve inflammation and facilitate tissue repair. Indeed, MuSCs can exert therapeutic effects on various degenerative and inflammatory disorders based on their immunoregulatory ability, including effects primed by interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). At the molecular level, the tryptophan metabolites, kynurenine or kynurenic acid, produced by indoleamine 2,3-dioxygenase (IDO), augment the expression of TNF-stimulated gene 6 (TSG6) through the activation of the aryl hydrocarbon receptor (AHR). In addition, insulin growth factor 2 (IGF2) produced by MuSCs can endow maturing macrophages oxidative phosphorylation (OXPHOS)-dependent anti-inflammatory functions. Herein, we summarize the current understanding of the immunomodulatory characteristics of MuSCs and the issues related to their potential applications in pathological conditions, including COVID-19.

Ubiquitination-mediated proteolysis or regulation of proteins, ultimately executed by E3 ubiquitin ligases, control a wide array of cellular processes, including transcription, cell cycle, autophagy and apoptotic cell death. HECT-type E3 ubiquitin ligases can be distinguished from other subfamilies of E3 ubiquitin ligases because they have a C-terminal HECT domain that directly catalyzes the covalent attachment of ubiquitin to their substrate proteins. Deregulation of HECT-type E3-mediated ubiquitination plays a prominent role in cancer development and chemoresistance. Several members of this subfamily are indeed frequently deregulated in human cancers as a result of genetic mutations and altered expression or activity. HECT-type E3s contribute to tumorigenesis by regulating the ubiquitination rate of substrates that function as either tumour suppressors or oncogenes. While the pathological roles of the HECT family members in solid tumors are quite well established, their contribution to the pathogenesis of hematological malignancies has only recently emerged. This review aims to provide a comprehensive overview of the involvement of the HECT-type E3s in leukemogenesis.

Serine and one-carbon unit metabolisms are essential biochemical pathways implicated in fundamental cellular functions such as proliferation, biosynthesis of important anabolic precursors and in general for the availability of methyl groups. These two distinct but interacting pathways are now becoming crucial in cancer, the de novo cytosolic serine pathway and the mitochondrial one-carbon metabolism. Apart from their role in physiological conditions, such as epithelial proliferation, the serine metabolism alterations are associated to several highly neoplastic proliferative pathologies. Accordingly, prostate cancer shows a deep rearrangement of its metabolism, driven by the dependency from the androgenic stimulus. Several new experimental evidence describes the role of a few of the enzymes involved in the serine metabolism in prostate cancer pathogenesis. The aim of this study is to analyze gene and protein expression data publicly available from large cancer specimens dataset, in order to further dissect the potential role of the abovementioned metabolism in the complex reshaping of the anabolic environment in this kind of neoplasm. The data suggest a potential role as biomarkers as well as in cancer therapy for the genes (and enzymes) belonging to the one-carbon metabolism in the context of prostatic cancer.

The skin is a peripheral lymphoid organ, being the first immunological defense against infections as the initial interface between the organism and the external background. The maintenance of the skin immune homeostasis depends on a finely equilibrium of well-regulated relations between different cells and exogenous pathogens. Inflammatory skin diseases are directly linked to the dysregulation of this equilibrium. The present review discusses the role of the immune system, of T cells, in the etiopathogenesis of psoriasis, illustrating a potential rationale for innovative therapeutic intervention.

Smyd2 lysine methyltransferase regulates monomethylation of histone and nonhistone lysine residues using S‐adenosylmethionine cofactor as the methyl donor. The nonhistone interactors include several tumorigenic targets, including p53. Understanding this interaction would allow the structural principles that underpin Smyd2‐mediated p53 methylation to be elucidated. Here, we performed μ‐second molecular dynamics (MD) simulations on binary Smyd2‐cofactor and ternary Smyd2‐cofactor‐p53 peptide complexes. We considered both unmethylated and monomethylated p53 peptides (at Lys370 and Lys372). The results indicate that (a) the degree of conformational freedom of the C‐terminal domain of Smyd2 is restricted by the presence of the p53 peptide substrate, (b) the Smyd2 C‐terminal domain shows distinct dynamic properties when interacting with unmethylated and methylated p53 peptides, and (c) Lys372 methylation confines the p53 peptide conformation, with detectable influence on Lys370 accessibility to the cofactor. These MD results are therefore of relevance for studying the biology of p53 in cancer progression.

Squamous cell carcinoma (SCC) is a treatment-refractory tumour which arises from the epithelium of diverse anatomical sites such as oesophagus, head and neck, lung and skin. Accumulating evidence has revealed a number of genomic, clinical and molecular features commonly observed in SCC of distinct origins. Some of these genetic events culminate in fostering the activity of Delta Np63, a potent oncogene which exerts its pro-tumourigenic effects by regulating specific transcriptional programmes to sustain malignant cell proliferation and survival. In this review, we will describe the genetic and epigenetic determinants underlying Delta Np63 oncogenic activities in SCC, and discuss some relevant transcriptional effectors of Delta Np63, emphasizing their impact in modulating the crosstalk between tumour cells and tumour microenvironment (TME).

Alterations in the molecular mechanisms of cell death are a common feature of cancer. These alterations enable malignant cells to survive intrinsic death signalling leading to accumulation of genetic aberrations and helping them to cope with adverse conditions. Regulated cell death has historically been exclusively associated with classical apoptosis; however, increasing evidence indicates that several alternative mechanisms orchestrate multiple death pathways, such as ferroptosis, entosis, necroptosis and immunogenic cell death, each with distinct underlying molecular mechanisms. Although pharmacological targeting of cell death pathways has been the subject of intensive efforts in recent decades with a dominant focus on targeting apoptosis, the identification of these novel death pathways has opened additional venues for intervention in cancer cells and the immune system. In this mini-review, we cover some recent progress on major recently emerged cell death modalities, emphasizing their potential clinical and therapeutic implications. We also discuss the interplay between cell death and immune response, highlighting the potential of the combination of traditional anticancer therapy and immunocheckpoint blockade. While attempting to stimulate discussion and draw attention to the possible clinical impact of these more recently emerged cell death modalities, we also cover the major progress achieved in translating strategies for manipulation of apoptotic pathways into the clinic, focusing on the attempts to target the anti-apoptotic protein BCL-2 and the tumour suppressor p53.

Genetics is at the basis of cancer initiation and evolution, but emerging evidence indicates that mutations are not sufficient to produce cancer, indicating a role for epigenetic contributions to the different stages of tumorigenesis. While the genetic tracks of cancer have been widely investigated, the epigenetic "drivers" remain a vague definition. Gene-environment interactions can produce gene-regulatory programs that dictate pathogenesis; this implies a reciprocal relationship where environmental factors contribute to genetic mechanisms of tumorigenesis (i.e. mutagenesis) and genetic factors influence the cellular response to extrinsic stress. In this review article, we attempt to summarise the most remarkable findings demonstrating a contribution of epigenetic factors as proper "drivers" of tumorigenesis. We also try to pose attention on the relevance of epigenetic mechanisms as downstream consequences of genes versus environment interaction. published

Breast cancer (BC) is the second leading cause of cancer death in women worldwide, and settings of specific prognostic factors and efficacious therapies are made difficult by phenotypic heterogeneity of BC subtypes. Therefore, there is a current urgent need to define novel predictive genetic predictors that may be useful for stratifying patients with distinct prognostic outcomes. Here, we looked for novel molecular signatures for triple negative breast cancers (TNBCs). By a bioinformatic approach, we identified a panel of genes, whose expression was positively correlated with disease-free survival in TNBC patients, namely IL18R1, CD53, TRIM, Jaw1, LTB, and PTPRCAP, showing specific immune expression profiles linked to survival prediction; most of these genes are indeed expressed in immune cells and are required for productive lymphocyte activation. According to our hypothesis, these genes were not, or poorly, expressed in different TNBC cell lines, derived from either primary breast tumours or metastatic pleural effusions. This conclusion was further supported in vivo, as immuno-histochemical analysis on biopsies of TNBC invasive ductal carcinomas highlighted differential expression of these six genes in cancer cells, as well as in intra- and peri-tumoral infiltrating lymphocytes. Our data open to the possibility that inter-tumour heterogeneity of immune markers might have predictive value; further investigations are recommended in order to establish the real power of cancer-related immune profiles as prognostic factors. Supplementary Information The online version contains supplementary material available at 10.1007/s12672-021-00401-0.

Funder: the National Key R&D Program of China [2018YFA0107500], National Natural Science Foundation of China [81530043, 81930085 and 31771260], the Scientific Innovation Project of the Chinese Academy of Sciences [XDA16020403], the Social Development Project of Jiangsu Province [BE2016671], and the State Key Laboratory of Radiation Medicine and Protection, Soochow University [GZN1201804 and GZN1201903]., Inflammatory factors such as IFNγ and TNFα could endow mesenchymal stem cells (MSCs) a potent immunomodulatory property, a process called licensing, but the mechanisms are not fully understood. We here found that glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), which converts inactive cortisone to the active cortisol and thereby regulates tissue glucocorticoid (GC) levels, was greatly upregulated by IFNγ and TNFα in human umbilical cord-derived MSCs (UC-MSCs) in a synergistic manner. While IFNγ alone was not able to induce HSD11B1, it could increase the activity of NF-kB and thus augment the upregulation of HSD11B1 by TNFα. Interestingly, the upregulation of HSD11B1 by IFNγ and TNFα also required glucocorticoid receptor. Furthermore, HSD11B1 was shown to be required for the expression of TNF-stimulated gene 6 (TSG-6), an important anti-inflammatory effector molecule of MSCs. Therefore, the inflammatory factors IFNγ and TNFα can promote GC metabolism and thereby drive the expression of anti-inflammatory factor TSG-6 in human UC-MSCs, forming a potential negative feedback loop. These findings help to understand the relationship between inflammation and GC metabolism.

The transcription factor p63 mediates distinct cellular responses, primarily regulating epithelial and oocyte biology. In addition to the two amino terminal isoforms, TAp63 and ΔNp63, the 3’-end of p63 mRNA undergoes tissue-specific alternative splicing that leads to several isoforms, including p63α, p63β and p63γ. To investigate in vivo how the different isoforms fulfil distinct functions at the cellular and developmental levels, we developed a mouse model replacing the p63α with p63β by deletion of exon 13 in the Trp63 gene. Here, we report that whereas in two organs physiologically expressing p63α, such as thymus and skin, no abnormalities are detected, total infertility is evident in heterozygous female mice. A sharp reduction in the number of primary oocytes during the first week after birth occurs as a consequence of the enhanced expression of the pro-apoptotic transcriptional targets Puma and Noxa by the tetrameric, constitutively active, TAp63β isoform. Hence, these mice show a condition of ovary dysfunction, resembling human primary ovary insufficiency. Our results show that the p63 C-terminus is essential in TAp63α-expressing primary oocytes to control cell death in vivo, expanding the current understanding of human primary ovarian insufficiency., The transcription factor p63 mediates different cellular responses affecting epithelial and oocyte biology. Here, the authors generate a mouse model (HET Δ13p63 mice) expressing the p63β isoform and show this affects ovary development, phenocopying a human syndrome, primary ovary insufficiency.

Cancer immunotherapy represents a major advance in the cure of cancer following the dramatic advancements in the development and refinement of chemotherapies and radiotherapies. In the recent decades, together with the development of early diagnostic techniques, immunotherapy has significantly contributed to improving the survival of cancer patients. The immune-checkpoint blockade agents have been proven effective in a significant fraction of standard therapy refractory patients. Importantly, recent advances are providing alternative immunotherapeutic tools that could help overcome their limitations. In this mini review, we provide an overview on the main steps of the discovery of classic immune-checkpoint blockade agents and summarise the most recent development of novel immunotherapeutic strategies, such as tumour antigens, bispecific antibodies and TCR-engineered T cells.