SEARCH · Search bioRxiv

Results for “Cancer Biology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 811 records · Page 45Linked to original sources

bioRxiv2018

Nucleotide and codon background mutability shape cancer mutational spectrum and advance driver mutation identification

Identifying driver mutations in cancer is notoriously difficult. To date, recurrence of a mutation in patients remains one of the most reliable markers of mutation driver status. However, some mutations are more likely to occur than others due to differences in background mutation rates arising from various forms of infidelity of DNA replication and repair machinery, endogenous, and exogenous mutagens.\n\nWe used cancer-type and mutagen-specific mutability to study the contribution of background processes of mutagenesis and DNA repair in shaping the observed mutational spectrum in cancer. We developed and tested probabilistic model that adjusts the number of mutation recurrences in patients by background mutability in order to find mutations which may be under selection in cancer.\n\nWe showed that observed recurrence frequency of cancer mutations scaled with the background mutability, especially for tumor suppressor genes. In oncogenes, however, highly recurring mutations were characterized by relatively low mutability, resulting in a U-shaped trend. Mutations not yet observed in any tumor had relatively low mutability values, indicating that background mutability might limit the mutation occurrence.\n\nWe compiled a dataset of missense mutations from 58 genes with experimentally validated functional and transforming impacts from different studies. We found that mutability of driver mutations was lower than the mutability of passengers and consequently adjusting mutation recurrence frequency by mutability significantly improved ranking of mutations and driver prediction. Even though no training on existing data was involved, our approach performed similar or better to the existing state-of-the-art methods.\n\nAvailabilityhttps://www.ncbi.nlm.nih.gov/research/mutagene/gene

cancer biology↗

bioRxiv2018

Bacteria-to-human protein networks reveal origins of endogenous DNA damage

DNA damage provokes mutations and cancer, and results from external carcinogens or endogenous cellular processes. Yet, the intrinsic instigators of DNA damage are poorly understood. Here we identify proteins that promote endogenous DNA damage when overproduced: the DNA-damaging proteins (DDPs). We discover a large network of DDPs in Escherichia coli and deconvolute them into six DNA-damage-causing function clusters, demonstrating DDP mechanisms in three: reactive-oxygen increase by transmembrane transporters, chromosome loss by replisome binding, and replication stalling by transcription factors. Their 284 human homologs are over-represented among known cancer drivers, and their expression in tumors predicts heavy mutagenesis and poor prognosis. Half of tested human homologs, when overproduced in human cells, promote DNA damage and mutation, with DNA-damaging mechanisms like those in E. coli. Together, our work reveals DDP networks that provoke endogenous DNA damage and may indicate functions of many human known and newly implicated cancer-promoting proteins.

cancer biology↗

bioRxiv2018

TP53 mutations promote immunogenic activity in breast cancer

BackgroundAlthough immunotherapy has recently achieved clinical successes in a variety of cancers, thus far there is no any immunotherapeutic strategy for breast cancer (BC). Thus, it is important to discover biomarkers for identifying the BC patients responsive to immunotherapy. TP53 mutations were often associated with worse clinical outcome in BC, of which the triple-negative BC (TNBC) has a high TP53 mutation rate (approximately 80%). TNBC is high-risk due to its high invasiveness, and lack of targeted therapy. To explore a potentially promising therapeutic option for the TP53-mutated BC subtype, we studied the associations between TP53 mutations and immunogenic activity in BC.\n\nMethodsWe compared enrichment levels of 26 immune gene-sets that indicated activities of diverse immune cells, functions, and pathways between TP53-mutated and TP53-wildtype BCs based on two large-scale BC multi-omics data. Moreover, we explored the molecular cues that were associated with the differences in immunogenic activity between TP53-mutated and TP53-wildtype BCs. Furthermore, we performed experimental validation of the findings from bioinformatics analysis.\n\nResultsWe found that almost all analyzed immune gene-sets had significantly higher enrichment levels in TP53-mutated BCs compared to TP53-wildtype BCs. Moreover, our experiments confirmed that mutant p53 could increase BC immunogenicity. Furthermore, our computational and experimental results showed that TP53 mutations could promote BC immunogenicity via regulation of the p53-mediated pathways including cell cycle, apoptosis, Wnt, Jak-STAT, NOD-like receptor, and glycolysis. Interestingly, we found that elevated immune activities were likely to be associated with better survival prognosis in TP53-mutated BCs, but not necessarily in TP53-wildtype BCs.\n\nConclusionsTP53 mutations promote immunogenic activity in breast cancer. This finding demonstrates a different effect of p53 dysfunction on tumor immunogenicity from that of previous studies, suggesting that the TP53 mutation status could be a useful biomarker for stratifying BC patients responsive to immunotherapy.

cancer biology↗

bioRxiv2018

IFN-γ induces epithelial-to-mesenchymal transition of cancer cells via an unique microRNA processing

Interferon-{gamma} (IFN{gamma}) is a potent cytokine in modulating tumor immunity and tumoricidal effects. We demonstrate a new function of IFN{gamma} in inducing epithelial-to-mesenchymal transition (EMT) in normal and cancer cells from different cell types. IFN{gamma} activates JAK-STAT signaling pathway leading to the transcription of IFN-stimulated genes (ISGs), such as interferon-induced tetratricopeptide repeat 5 (IFIT5). We unveil a new function of IFIT5 complex in degrading precursor microRNAs (pre-miRNA) that include pre-miR-363 from the miR-106a-363 cluster, as well as pre-miR-101 and pre-miR-128 with a similar 5-end structure with pre-miR-363. Noticeably, these suppressive miRNAs have similar functions by targeting EMT transcription factors in prostate cancer (PCa) cells. We further demonstrated that IFIT5 plays a critical role in IFN{gamma}-induced cell invasiveness in vitro and lung metastasis in vivo. Clinically, IFIT5 is highly elevated in high-grade PCa and its expression inversely correlates with these suppressive miRNAs. Altogether, this study unveils pro-tumorigenic role of the IFN pathway via a new mechanism of action, which certainly raises concern about its clinical application.

cancer biology↗

bioRxiv2018

Follicle stimulating hormone is an autocrine regulator of the ovarian cancer metastatic niche through Notch signaling

The association between the upregulated Notch and FSH signaling and ovarian cancer is well documented. However, their signaling has been investigated independently and only in the primary tumor tissues. The aim of this study was to investigate the interactive effects of FSH and Notch signaling on the ovarian cancer proliferation, formation and maintenance of the disseminated ovarian cancer cells. Roles of Notch and FSH in the ovarian cancer pathogenesis was investigated using ovarian cancer cell lines and specific antibodies against Notch and FSH receptor (FSHR). FSH upregulated Notch signaling and proliferation in the ovarian cancer cells. High levels of FSH were detected in the ascites of patients with serous ovarian adenocarcinoma. The spheroids from the ascites of the patients, as well as, the spheroids from the ovarian cancer cell lines under low attachment culture conditions, expressed FSH{beta} subunit mRNAs and secreted the hormone into the medium. In contrast, the primary ovarian tumor tissues and cell line monolayers expressed very low levels of FSH{beta}. The ovarian cancer cell spheroids also exhibited higher expression of the FSH receptor and Notch downstream genes than their monolayer counterparts. A combination of FSHR and Notch antagonistic antibodies significantly inhibited spheroid formation and cell proliferation in vitro. This study demonstrates that spheroids in ascites express and secrete FSH, which regulates cancer cell proliferation and spheroidogenesis through Notch signaling, suggesting that FSH is an autocrine regulator of cancer metastasis. Further, Notch and FSHR are potential immunotherapeutic targets for ovarian cancer treatment.

cancer biology↗

bioRxiv2018

DNA methylation signature of smoking in lung cancer is enriched for exposure signatures in newborn and adult blood.

BackgroundSmoking impacts DNA methylation genome-wide in blood of both newborns from maternal smoking during pregnancy and adults from personal smoking. Smoking causes lung cancer which involves aberrant methylation. We examined whether DNA methylation smoking signatures identified in blood of newborns and adults are detectable in lung tumors.\n\nMethodsWe compared smoking-related DNA methylation in lung adenocarcinomas (61 never smokers, 91 current smokers, and 238 former smokers) quantified with the Illumina450k BeadArray in The Cancer Genome Atlas with published large consortium meta-analyses of newborn and adult blood. We assessed whether CpG sites related to smoking in blood from newborns and adults were enriched in lung adenocarcinoma.\n\nResultsTesting CpGs differentially methylated by smoke exposure (P<10-4) we identified 296 in lung tumors, while previous meta-analyses (False Discovery Rate (FDR)<0.05) identified 6,073 in newborn blood, and for adult smoking, 18,760 in blood. The lung signals were highly enriched for those seen in newborn (32 overlapping, Penrichment=1.2x10-19) and adult blood (86 overlapping, Penrichment = 9.5x10-49). The 65 genes annotated to CpGs differentially methylated in lung tumors, but not blood, were enriched for RNA processing ontologies.\n\nConclusionsWe found highly significant overlap between smoking-related DNA methylation signals in lung cancer and those seen in blood from newborns, from in utero exposure, or adults, from their own exposure. These results suggest that some epigenetic alterations associated with cigarette smoke exposure are tissue specific, but others are common across tissues. These findings support the value of blood-based methylation biomarkers for assessing exposure effects in target tissues.

cancer biology↗

bioRxiv2018

Developmental-stage-specific proliferation and retinoblastoma genesis in RB-deficient human but not mouse cone precursors

Most retinoblastomas initiate in response to the inactivation of the RB1 gene and loss of functional RB protein. The tumors may form without additional genomic changes and develop after a pre-malignant retinoma phase. Despite this seemingly straightforward etiology, mouse models have not recapitulated the genetic, cellular, and stage-specific features of human retinoblastoma genesis. For example, whereas human retinoblastomas appear to derive from cone photoreceptor precursors, current mouse models develop tumors that derive from other retinal cell types. To investigate the basis of the human cone-specific oncogenesis, we compared developmental-stage-specific cone precursor responses to RB loss in human and murine retina cultures and in cone-specific Rb1 knockout mice. We report that RB-depleted maturing (ARR3+) but not immature (ARR3-) human cone precursors enter the cell cycle, proliferate, and form retinoblastoma-like lesions characterized by Flexner-Wintersteiner rosettes, then form low or non-proliferative pre-malignant retinoma-like lesions with fleurettes and high p16INK4A and p130 expression, and finally form highly proliferative retinoblastoma-like masses. In contrast, in murine retina, only RB-depleted immature (Arr3-) cone precursors entered the cell cycle and they failed to progress from S to M phase. Moreover, whereas the intrinsically highly expressed MDM2 and MYCN contribute to RB-depleted maturing (ARR3+) human cone precursor proliferation, ectopic MDM2 and Mycn promoted only immature (Arr3-) murine cone precursor cell cycle entry. These findings demonstrate that developmental-stage-specific as well as speciesand cell-type-specific features sensitize to RB1 inactivation and reveal the human cone precursors capacity to model retinoblastoma initiation, proliferation, pre-malignant arrest, and tumor growth.\n\nSignificance StatementRetinoblastoma is a childhood tumor that forms in response to mutations in the RB1 gene and loss of functional RB protein. Prior studies suggested that retinoblastomas arise from cone photoreceptor precursors, whereas mouse models yield tumors deriving from other retinal cell types and lacking human retinoblastoma features. Here, we show that in cultured human retinae, retinoblastomas initiate from RB-depleted cone precursors that are in a specific maturation state and form pre-malignant \"retinomas\" prior to retinoblastoma lesions, as is believed to occur in retinoblastoma patients. In contrast, Rb-deficient mouse cone precursors of similar maturation state and supplemented with human-cone-precursor-specific oncoproteins fail to proliferate. Thus, human species-specific developmental features underlie retinoblastomagenesis and may challenge the production of accurate mouse retinoblastoma models.

cancer biology↗

bioRxiv2018

The proto CpG island methylator phenotype of sessile serrated adenoma/polyps

Sessile serrated adenomas/polyps (SSA/Ps) are the putative precursors of the {small tilde}20% of colon cancers with the CpG island methylator phenotype (CIMP), but their molecular features are poorly understood. We used high-throughput analysis of DNA methylation and gene expression to investigate the epigenetic phenotype of SSA/Ps. Fresh-tissue samples of 17 SSA/Ps and (for comparison purposes) 15 conventional adenomas (cADNs)--each with a matched sample of normal mucosa-- were prospectively collected during colonoscopy (total no. samples analyzed: 64). DNA and RNA were extracted from each sample. DNA was subjected to bisulfite next-generation sequencing to assess methylation levels at {small tilde}2.7 million CpG sites located predominantly in gene regulatory regions and spanning 80.5Mb ({small tilde}2.5% of the genome); RNA was sequenced to define the samples transcriptomes. An independent series of 61 archival lesions was used for targeted verification of DNA methylation findings. Compared with normal mucosa samples, SSA/Ps and cADNs exhibited markedly remodeled methylomes. In cADNs, hypomethylated regions were far more numerous (18,417 vs 4288 in SSA/Ps) and rarely affected CpG islands/shores. SSA/Ps seemed to have escaped this wave of demethylation. Cytosine hypermethylation in SSA/Ps was more pervasive (hypermethylated regions: 22,147 vs 15,965 in cADNs; hypermethylated genes: 4938 vs 3443 in cADNs) and more extensive (region for region), and it occurred mainly within CpG islands and shores. Given its resemblance to the CIMP typical of SSA/Ps putative descendant colon cancers, we refer to the SSA/P methylation phenotype as proto-CIMP. Verification studies of six hypermethylated regions (3 SSA/P-specific and 3 common) demonstrated the high potential of DNA methylation markers for predicting the diagnosis of SSA/Ps and cADNs. Surprisingly, proto-CIMP in SSA/Ps was associated with upregulated gene expression (n=618 genes vs 349 that were downregulated); downregulation was more common in cADNs (n=712 vs 516 upregulated genes). The epigenetic landscape of SSA/Ps differs markedly from that of cADNs. These differences are a potentially rich source of novel tissue-based and noninvasive biomarkers that can add precision to the clinical management of the two most frequent colon-cancer precursors.

cancer biology↗

bioRxiv2018

Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, compensates for p53 loss and induces apoptosis in TP53-deficient cancer cells.

BackgroundThe p73 protein is a tumor suppressor that shares structural and functional similarity with p53. p73 is expressed in two major isoforms; the TA isoform that interacts with p53 pathway, thus acting as tumor suppressor and the N-terminal truncated {Delta}N isoform that inhibits TAp73 and p53 and thus, acts as an oncogene.\n\nResultsBy employing a drug repurposing approach, we found that protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid (ALA) applied in photodynamic therapy of cancer, stabilizes TAp73 and activates TAp73-dependent apoptosis in cancer cells lacking p53. The mechanism of TAp73 activation is via disruption of TAp73/MDM2 and TAp73/MDMX interactions and inhibition of TAp73 degradation by ubiquitin ligase Itch.\n\nConclusionOur findings may in future contribute to the successful repurposing of PpIX into clinical practice.

cancer biology↗

bioRxiv2018

Radiotherapy and cisplatin increase immunotherapy efficacy by enabling local and systemic intratumoral T-cell activity

To increase cancer immunotherapy success, PD-1 blockade must be combined with rationally selected treatments. Here, we examined in a poorly immunogenic mouse breast cancer model the potential of antibody-based immunomodulation and conventional anti-cancer treatments to collaborate with anti-PD-1 treatment. One important requirement to improve anti-PD-1-mediated tumor control was to promote tumor-specific cytotoxic T cell (CTL) priming, which was achieved by stimulating the CD137 costimulatory receptor. A second requirement was to overrule PD-1-unrelated mechanisms of CTL suppression in the tumor micro-environment (TME). This was achieved by radiotherapy and cisplatin treatment. In the context of CD137/PD-1-targeting immunotherapy, radiotherapy allowed for tumor elimination by altering the TME, rather than intrinsic CTL functionality. Combining this radioimmunotherapy regimen with low-dose cisplatin improved CTL-dependent regression of a contralateral tumor outside the radiation field. Thus, systemic tumor control may be achieved by combining immunotherapy protocols that promote T cell priming with (chemo)radiation protocols that permit CTL activity in both the irradiated tumor and (occult) metastases.\n\nSummary statementThis study reveals that radiotherapy and cisplatin can be re-purposed to improve antibody-based immunotherapy success in poorly immunogenic breast cancer by overruling PD-1 unrelated mechanisms of T cell suppression in the tumor micro-environment.

cancer biology↗

bioRxiv2018

Kunitz type protease inhibitor EgKI-1 from the canine tapeworm Echinococcus granulosus as a promising anti-cancer therapeutic

EgKI-1, a member of the Kunitz type protease inhibitor family, is highly expressed by the oncosphere of the canine tapeworm Echinococcus granulosus, the stage that is infectious to humans and ungulates, giving rise to a hydatid cyst localized to the liver and other organs. Larval protoscoleces, which develop within the hydatid cyst, have been shown to possess anti-cancer properties, although the precise molecules involved have not been identified. We show that recombinant EgKI-1 inhibits the growth and migration of a range of human cancers including breast, melanoma and cervical cancer cell lines in a dose-dependent manner in vitro without affecting normal cell growth. Furthermore, EgKI-1 treatment arrested the cancer cell growth by disrupting the cell cycle and induced apoptosis of cancer cells in vitro. An in vivo model of triple negative breast cancer (MDA-MB-231) in BALB/c nude mice showed significant tumor growth reduction in EgKI-1-treated mice compared with controls. These findings indicate that EgKI-1 shows promise for future development as an anti-cancer therapeutic.

cancer biology↗

bioRxiv2018

Regulation of checkpoint kinase signalling and tumorigenesis by the NF-κB regulated gene, CLSPN

Inhibition of the tumour promoting activities of NF-{kappa}B by cell signalling pathways has been proposed as a natural mechanism to limit the development of cancer. However, there has been a lack of evidence for these effects in vivo. Here we report that RelAT505A mice, where a CHK1 targeted Thr505 phosphosite is mutated to alanine, display earlier onset of MYC driven lymphoma than wild type littermates. We describe a positive feedback loop in which the NF-{kappa}B subunits RelA and c-Rel, in a manner dependent upon RelA Thr505 phosphorylation, drive the expression of the ATR checkpoint kinase regulator Claspin in response to DNA replication stress in cancer cells. This in turn is required for maintenance of CHK1 activity. Loss of a single allele of the Clspn gene in mice is sufficient to drive earlier tumorigenesis and low levels of CLSPN mRNA expression are associated with worse survival in some forms of human cancer. We propose that loss of this pathway early in tumorigenesis promotes cancer development through increased genomic instability. However, in malignant cancer cells it can help promote their addiction to the checkpoint kinase signalling required for the maintenance of genomic integrity. Importantly, disruption of this pathway leads to resistance of cells to treatment with CHK1 inhibitors. Claspin expression could therefore act as a biomarker for responsiveness of patients to CHK1 inhibitors and provide a potential pathway for the development of tumour resistance.

cancer biology↗

bioRxiv2018

Multidimensional transcriptomics provides detailed information about immune cell distribution and identity in HER2+ breast tumors

The comprehensive analysis of tumor tissue heterogeneity is crucial for determining specific disease states and establishing suitable treatment regimes. Here, we analyze tumor tissue sections from ten patients diagnosed with HER2+ breast cancer. We obtain and analyze multidimensional, genome-wide transcriptomics data to resolve spatial immune cell distribution and identity within the tissue sections. Furthermore, we determine the extent of immune cell infiltration in different regions of the tumor tissue, including invasive cancer regions. We combine cross-sectioning and computational alignment to build three-dimensional images of the transcriptional landscape of the tumor and its microenvironment. The three-dimensional data clearly demonstrates the heterogeneous nature of tumor-immune interactions and reveal interpatient differences in immune cell infiltration patterns. Our study shows the potential for an improved stratification and description of the tumor-immune interplay, which is likely to be essential in treatment decisions.

cancer biology↗

bioRxiv2018

Low MSH2 protein levels identify muscle-invasive bladder cancer resistant to cisplatin

BackgroundThe response to first-line, platinum-based treatment of muscle-invasive bladder cancer has not improved in three decades.\n\nObjectiveThe objective of this study is to identify genes that predict cisplatin resistance in bladder cancer.\n\nDesignWe performed a whole-genome, CRISPR-based screen in a bladder cancer cell line treated with cisplatin to identify genes that mediate response to cisplatin. Targeted validation was performed in vitro across two bladder cancer cell lines. The top gene candidate was validated in a publicly available bladder cancer dataset containing 340 bladder cancer patients with treatment, protein, and survival information.\n\nResults and limitationsThe cisplatin resistance screen suggested the mismatch repair pathway through the loss of MSH2 and MLH1 contribute to cisplatin resistance. Bladder cancer cells depleted of MSH2 are resistant to cisplatin in vitro, in part due to a reduction in apoptosis. These cells maintain sensitivity to the cisplatin-analog, oxaliplatin. Bladder tumors with low protein levels of MSH2 have poorer overall survival when treated with cisplatin- or carboplatin-based therapy.\n\nConclusionsWe generated in vitro and clinical support that bladder cancer cell lines and tumors with low levels of MSH2 are more resistant to cisplatin-based therapy. Further studies are warranted to determine the ability of MSH2 protein levels to serve as a prospective biomarker of chemotherapy response in bladder cancer.\n\nPatient summaryWe report the first evidence that the protein level of MSH2 may contribute to chemotherapy resistance observed in bladder cancer. MSH2 levels has the potential to serve as a biomarker of treatment response.

cancer biology↗

bioRxiv2018

Identification of circulating protein biomarkers for pancreatic cancer cachexia

BackgroundOver 80% of patients with pancreatic ductal adenocarcinoma (PDAC) suffer from cachexia, characterized by severe muscle and fat loss. Although various model systems have improved our understanding of cachexia, translating the findings to human cachexia has remained a challenge. In this study, our objectives were to i) identify circulating protein biomarkers using serum for human PDAC cachexia, (ii) identify the ontological functions of the identified biomarkers and (iii) identify new pathways associated with human PDAC cachexia by performing protein co-expression analysis.\n\nMethodsSerum from 30 patients with PDAC was collected. Body composition measurements of skeletal muscle index (SMI), skeletal muscle density (SMD), total adipose index (TAI) were obtained from computed tomography scans (CT). Cancer associated weight loss (CAWL), an ordinal classification of history of weight loss and body mass index (BMI) was obtained from medical record. Serum protein profiles and concentrations were generated using SOMAscan, a quantitative aptamer-based assay. Ontological analysis of the proteins correlated with clinical variables (r[≥] 0.5 and p<0.05) was performed using DAVID Bioinformatics. Protein co-expression analysis was determined using pairwise Spearmans correlation.\n\nResultsOverall, 111 proteins of 1298 correlated with these clinical measures, 48 proteins for CAWL, 19 for SMI, 14 for SMD, and 30 for TAI. LYVE1, a homolog of CD44 implicated in tumor metastasis, was the top CAWL-associated protein (r= 0.67, p=0.0001). Other proteins such as INHBA, MSTN/GDF11, and PIK3R1 strongly correlated with CAWL. Proteins correlated with cachexia included those associated with proteolysis, acute inflammatory response, as well as B cell and T cell activation. Protein co-expression analysis identified networks such as activation of immune related pathways such as B-cell signaling, Th1 and Th2 pathways, natural killer cell signaling, IL6 signaling, and mitochondrial dysfunction.\n\nConclusionTaken together, these data both identify immune system molecules and additional secreted factors and pathways not previously associated with PDAC and confirm the activation of previously identified pathways. Identifying altered secreted factors in serum of PDAC patients may assist in developing minimally invasive laboratory tests for clinical cachexia as well as identifying new mediators.

cancer biology↗

bioRxiv2018

VPAC1 couples with TRPV4 channel to promote calcium-dependent gastric cancer progression

Although VPAC1 and its ligand vasoactive intestinal peptide (VIP) are important in gastrointestinal physiology, their involvements in progression of gastrointestinal tumor have not been explored. Here, we found that higher expression of VIP/VPAC1 was observed in gastric cancer compared to the adjacent normal tissues. The increased expression of VIP/VPAC1 in gastric cancer correlated positively with invasion, tumor stage, lymph node, distant metastases, and poor survival. Moreover, high expression of VIP and VPAC1, advanced tumor stage and distant metastasis were independent prognostic factors. VPAC1 activation by VIP markedly induced TRPV4-mediated Ca2+ entry, and eventually promoted gastric cancer progression in a Ca2+ signaling-dependent manner. Inhibition of VPAC1 and its signaling pathway could block the progressive responses. VPAC1/TRPV4/Ca2+ signaling in turn enhanced the expression and secretion of VIP in gastric cancer cells, enforcing a positive feedback regulation mechanism. Taken together, our study demonstrate that VPAC1 is significantly overexpressed in gastric cancer and VPAC1/TRPV4/Ca2+ signaling axis could enforce a positive feedback regulation in gastric cancer progression. VIP/VPAC1 may serve as potential prognostic markers and therapeutic targets for gastric cancer.

cancer biology↗

bioRxiv2018

Cancer cell exosomes can initiate malignant cell transformation

Cancer evolves through a multistep process that occurs by the temporal accumulation of genetic mutations mediated by intracellular and extracellular cues. We observe that exosomes isolated from pancreatic cancer cells, but not normal pancreatic cells, can initiate the first step of malignant cell transformation. Injection of exosome-initiated transformed cells into mice results in aggressive tumor growth. Using proteomic profiling and DNA sequencing of exosome-treated and transformed cells, we show that cancer cell exosomes act as a classic initiator by causing random genetic changes in recipient cells. Our studies provide new insight into a function of cancer cell exosomes and how they might specifically contribute to orchestrated local cell transformation.\n\nOne Sentence SummaryExosomes function as an initiator of tumor formation.

cancer biology↗

bioRxiv2018

DNMT3A-NPM1 mutated acute myeloid leukaemia shows sensitivity to a PARP1 inhibitor combined with daunorubicin in an in vitro model

Acute myeloid leukaemia is a neoplasia in need of new treatment approaches. PARP inhibitors are a class of targeted therapeutics for cancer that disrupts dysfunctional DNA damage response in various neoplasia. MLL-AF9 mutated leukaemias are sensitive to combinations of PARP inhibitors and cytotoxic drugs. Moreover, DNMT3A and NPM1 mutations are linked to dysfunctions in DNA damage response. Therefore, we investigated if DNMT3A-NPM1 mutated AML cell line is sensible to PARP inhibitors combined with anthracyclines. Our results show that DNMT3A-NPM1 mutated AML is as sensible to combinations of PARP inhibitors and anthracyclines as MLL-AF9 mutated leukaemias, in an in vitro setting.

cancer biology↗