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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2018

Non-driver somatic alteration burden confers good prognosis in non-small cell lung cancer

BackgroundGenomic profiling of patient tumors has linked somatic driver mutations to survival outcomes of non-small cell lung cancer (NSCLC) patients, especially for those receiving targeted therapies. However, it remains unclear whether specific non-driver mutations have any prognostic utility.\n\nMethodsWhole exomes and transcriptomes were measured from NSCLC xenograft models of patients with diverse clinical outcomes. Penalised regression analysis was performed to identify a set of 865 genes associated with patient survival. The number of somatic copy number aberrations, point mutations and associated expression changes within the 865 genes were used to stratify independent NSCLC patient populations, filtered for chemotherapy naive and early-stage. In-depth genomic analysis and functional testing was conducted on the genomic alterations to understand their effect on improving survival.\n\nResultsHigh burden of somatic alterations are associated with longer disease-free survival (HR=0.153, P=1.48x10-4) in NSCLC patients. When somatic alterations burden was integrated with gene expression, we were able to predict prognosis in three independent patient datasets. Patients with high alteration burden could be further stratified based on the presence of immunogenic mutations, revealing another subgroup of patients with even better prognosis (85% with >5 years survival), and associated with cytotoxic T-cell expression. In addition, 95% of these 865 genes lack documented activity relevant to cancer, but are in pathways regulating cell proliferation, motility and immune response were implicated.\n\nConclusionOur results demonstrate that non-driver somatic alterations may influence the outcome of cancer patients by increasing beneficial immune response and inhibiting processes associated to tumorigenesis.

cancer biology↗

bioRxiv2018

Optimization of Dose Schedules for Chemotherapy of Early Colon Cancer Determined by High Performance Computer Simulations

Cancer chemotherapy dose schedules are conventionally applied intermittently, with dose duration of the order of hours, intervals between doses of days or weeks, and cycles repeated for weeks. The large number of possible combinations of values of duration, interval, and lethality has been an impediment to empirically determine the optimal set of treatment conditions. The purpose of this project was to determine the set of parameters for duration, interval, and lethality that would be most effective for treating early colon cancer. An agent-based computer model that simulated cell proliferation kinetics in normal human colon crypts was calibrated with measurements of human biopsy specimens. Mutant cells were simulated as proliferating and forming an adenoma, or dying if treated with cytotoxic chemotherapy. Using a high performance computer, a total of 28,800 different parameter sets of duration, interval, and lethality were simulated. The effect of each parameter set on the stability of colon crypts, the time to cure a crypt of mutant cells, and the accumulated dose was determined. Of the 28,800 parameter sets, 434 parameter sets were effective in curing the crypts of mutant cells before they could form an adenoma and allowed the crypt normal cell dynamics to recover to pretreatment levels. A group of 14 similar parameter sets produced a minimal time to cure mutant cells. A different group of 9 similar parameter sets produced the least accumulated dose. These parameter sets may be considered as candidate dose schedules to guide clinical trials for early colon cancer.

cancer biology↗

bioRxiv2018

Dihydropyrimidinase protects from DNA replication stress caused by cytotoxic metabolites.

Metabolic alterations support cellular transformation. Noticeably, cellular transformation and cancer progression is associated with accumulation of dihydrouracil and dihydrothymine. However, it remains elusive how dihydropyrimidine metabolites affect cellular phenotypes. Dihydropyrimidines are degraded by dihydropyrimidinase (DHP). This zinc metalloenzyme is upregulated in solid tumors but not in the corresponding normal tissues. Here we show that DHP silencing in transformed cell lines is cytotoxic. Increasing the level of dihydropyrimidines inhibited DNA replication and transcription. It induced replication stress signaling by ATR and p53 stabilization. Remarkably, cells lacking DHP accumulated DNA-protein crosslinks (DPCs). Among DPCs, covalently trapped translesion DNA polymerase {eta} contributed to the cytotoxicity of dihydropyrimidines. Furthermore, we show that the plant flavonoid dihydromyricetin inhibits the activity of recombinant human DHP. Cellular treatment with dihydromyricetin triggered DPCs-dependent DNA replication stress. This study defines dihydropyrimidines as potentially cytotoxic metabolites that may offer an opportunity for therapeutic-targeting of DHP activity in solid tumors.

cancer biology↗

bioRxiv2018

Molecular measurable residual disease testing of blood during AML cytotoxic therapy for early prediction of clinical response

AbstractO_ST_ABSPURPOSEC_ST_ABSMeasurable residual disease (MRD) testing after initial chemotherapy treatment can predict relapse and survival in AML. However, it has not been established if repeat molecular or genetic testing during chemotherapy can offer information regarding the chemotherapy sensitivity of the leukemic clone.\n\nPATIENTS AND METHODSBlood from 45 adult AML patients at day 1 and 4 of induction (n = 35) or salvage (n = 10) cytotoxic chemotherapy was collected for both quantitative real-time PCR (qPCR) assessment (WT1) and next generation sequencing (NGS, >500x depth) of 49 gene regions recurrently mutated in MDS/AML.\n\nRESULTSThe median age was 62 (23-78); 42% achieved a complete response. WT1 was overexpressed in most patients tested but was uninformative for very early MRD assessment. A median of 4 non-synonymous variants (range 0-7) were detected by DNA sequencing of blood on day 1 of therapy (median VAF: 29%). Only two patients had no variants detectable. All mutations remained detectable in blood on day 4 of intensive chemotherapy and remarkably the ratio of mutated to wild-type sequence was often maintained. This phenomenon was not limited to variants in DNMT3A, TET2 and ASXL1. The kinetics of NPM1 and TP53 variant burden early during chemotherapy appeared to be exceptions and exhibited consistent trends in this cohort.\n\nCONCLUSIONSMolecular testing of blood on day 4 of chemotherapy is not predictive of clinical response in AML. The observed stability in variant allele frequency suggests that cytotoxic therapy may have a limited therapeutic index for clones circulating in blood containing these mutations. Further validation is required to confirm the utility of monitoring NPM1 and TP53 kinetics in blood during cytotoxic therapy.

cancer biology↗

bioRxiv2018

STAT3 promotes melanoma metastasis by CEBP-induced repression of the MITF pigmentation pathway

Metastatic melanoma is hallmarked by its ability to switch oncogenic MITF expression. Here we tested the impact of STAT3 on melanoma onset and progression in association with MITF expression levels. We established a mouse melanoma model for deleting Stat3 specifically in melanocytes with specific expression of human hyperactive NRASQ61K in an Ink4a deficient background. Mice with tissue specific Stat3 deletion showed an early onset of disease, but displayed significantly diminished lung metastases. Whole genome expression profiling also revealed a reduced invasion phenotype, which was functionally confirmed in 3D melanoma model systems. Notably, loss or knockdown of STAT3 in mouse or human cells resulted in up-regulation of MITF and induction of cell proliferation. Mechanistically we show that STAT3 induced CEBPa/b expression was sufficient to suppress MITF transcription. Epigenetic analysis by ATAC-seq confirmed that STAT3 enabled CEBPa/b binding to the MITF enhancer region thereby silencing it. We conclude that STAT3 is a metastasis driver in melanoma able to antagonize the MITF oncogene via direct induction of CEBP family member transcription facilitating RAS-RAF-driven melanoma metastasis.\n\nList of Abbreviations\n\nATAC-seq, Assay for Transposase-Accessible Chromatin using sequencing; CEBP, CAAT Box Enhancer Binding Protein; CRE, Cre recombinase; EGF, Epidermal Growth Factor; GEO, Gene Expression Omnibus; GSEA, Gene Set Enrichment Analysis; HSC70, Heat Shock 70 kDa protein; IHC, Immunohistochemistry; IL-6, Interleukin-6; JAK, Janus Kinase; MITF, Microphthalmia-Associated Transcription Factor; NSG, NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice; OSM, Oncostatin M; PDGF, Platelet-Derived Growth Factor; pS, phosphoserine; pY, phosphotyrosine; RAS, Rat Sarcoma; RAF, Rapidly Accelerated Fibrosarcoma; RTK, Receptor Tyrosine Kinase; RT-PCR, Reverse Transcription Polymerase Chain Reaction; S100b, Calcium Binding Protein S100 beta; shRNA, short hairpin RNA; SOX10, Sex Determining Region Y-10; STAT, Signal Transducer and Activator of Transcription; TCGA, The Cancer Genome Atlas; TMA, Tissue Micro Array

cancer biology↗

bioRxiv2018

HBx enhances CPAP expression via interacting with CREB to promote hepatocarcinogenesis in HBV-associated HCC

Hepatitis B virus (HBV) encoded non-structure protein X (HBx) can promote cell proliferation, migration, and anti-apoptosis via activating several transcription factors and increasing their downstream gene expression in HBV-infected liver cells. Our previous report suggested that centrosomal P4.1-associated protein (CPAP) is required for HBx-mediated NF-{kappa}B activation. Here, we found that, upon HBV infection, overexpressed HBx can transcriptionally up-regulate CPAP via interacting with CREB. CPAP can directly interact with HBx to promote HBx-mediated cell proliferation and migration; and SUMO modification of CPAP is involved in interacting with HBx. Interestingly, CPAP can increase the HBx protein stability in an NF-{kappa}B-dependent manner; and overexpressed CPAP and HBx is positively correlated with the activation status of NF-{kappa}B in HCC. Increased expression of CREB and CPAP mRNAs exists in the high-risk group with a lower survival rate in hepatocellular carcinoma (HCC). These results suggest that the reciprocal regulation between CPAP and HBx may provide a microenvironment to facilitate HCC development via enhancing NF-{kappa}B activation, inflammatory cytokine production, and cancer maligancies. The findings of this study not only shed light on the role of CPAP in HBV-associated HCC, but also provide CPAP as a potential target for HBV-related HCC therapy.\n\nAuthor SummaryIn this study, we address a novel molecular mechanism for the collaboration between overexpressed HBx and CPAP in promoting hepatocarcinogenesis in HBV-associated HCC. Upon HBV infection, HBx is overexpressed and interacts with CREB to transcriptionally activate CPAP; the HBx/CPAP interaction promotes hepatocarcinogenesis. Clinical analysis found that co-overexpressed CPAP and CREB exist in the high-risk group with a lower survival rate in HCC. Additionally, overexpressed CPAP contributes to HBx protein stability in a NF-{kappa}B-dependent pathway. Our study provides a potential translational application in targeting CREB-CPAP axis in HBV-associated HCC.

cancer biology↗

bioRxiv2018

RUNX proteins desensitize multiple myeloma to lenalidomide via protecting IKZFs from degradation

Ikaros family zinc finger protein 1 and 3 (IKZF1 and IKZF3) are transcription factors that promote multiple myeloma (MM) proliferation. The immunomodulatory imide drug (IMiD) lenalidomide promotes myeloma cell death via Cereblon (CRBN)-dependent ubiquitylation and proteasome-dependent degradation of IKZF1 and IKZF3. Although IMiDs have been used as first-line drugs for MM, the overall survival of refractory MM patients remains poor and demands the identification of novel agents to potentiate the therapeutic effect of IMiDs. Using an unbiased screen based on mass spectrometry, we identified the Runt-related transcription factor 1 and 3 (RUNX1 and RUNX3) as interactors of IKZF1 and IKZF3. Interaction with RUNX1 and RUNX3 inhibits CRBN-dependent binding, ubiquitylation and degradation of IKZF1 and IKZF3 upon lenalidomide treatment. Inhibition of RUNXs, via genetic ablation or a small molecule (AI-10-104), results in sensitization of myeloma cell lines and primary tumors to lenalidomide. Thus, RUNX inhibition represents a valuable therapeutic opportunity to potentiate IMiDs therapy for the treatment of multiple myeloma.

cancer biology↗

bioRxiv2018

TSLP-mediated inflammatory factors production contributes to metastatic breast cancer-induced bone cancer pain in mice

ObjectiveMetastatic breast cancer-induced bone cancer pain (BCP) is one of the most disabling factors in patients suffering. Recent studies show thymic stromal lymphopoietin (TSLP) is a proinflammatory factor and high expression in cancer cells. Here we investigated whether and how TSLP released form breast cancer cells contributes to BCP.\n\nMethodsBraset cancer cells MDA-MB-231 were intramedullary injected into the femur to induce BCP, TSLP neutralizing antibody was intrathecally injected and pain hypersensitivity was checked by behavioral testing. The TSLP expression was knockdown by shRNA. Human TSLP, TNF-, IL-1{beta}, IL-6, CCL2, CXCL2 and CXCL5 in intramedullary space of the femur of rats was detected by ELISA.\n\nResultsTSLP neutralizing antibody intrathecally injection significantly reduced MDA-MB-231 cells inoculation induced persistent mechanical allodynia and heat hyperalgesia and TSLP increased. Furthermore, Persistent mechanical allodynia and heat hyperalgesia of mice models were also decreased in MDA-MB-231 cells with TSLP knockdown. Finally, some inflammatory factors, TNF-, IL-1{beta}, IL-6, CCL2, CXCL2 and CXCL5 were significantly elevated in the intramedullary space lavage fluid of the right femur after cancer cell inoculation, but were obviously reduced in models with neutralizing antibody of TSLP treatment and TSLP knockdown.\n\nConclusionTSLP-mediated inflammatory factors release contributes to the maintenance of tumoral hypersensitivity. Inhibition of the TSLP may provide a new therapy for BCP management.

cancer biology↗

bioRxiv2018

MYCN-induced metabolic rewiring creates novel therapeutic vulnerabilities in neuroblastoma

MYCN is a transcription factor that is aberrantly expressed in many tumor types and is often correlated with poor patient prognosis. Recently, several lines of evidence pointed to the fact that oncogenic activation of MYC family proteins is concomitant with reprogramming of tumor cells to cope with an enhanced need for metabolites during cell growth. These adaptions are driven by the ability of MYC proteins to act as transcriptional amplifiers in a tissue-of-origin specific manner. Here, we describe the effects of MYCN overexpression on metabolic reprogramming in neuroblastoma cells. Ectopic expression of MYCN induced a glycolytic switch that was concomitant with enhanced sensitivity towards 2-deoxyglucose, an inhibitor of glycolysis. Moreover, global metabolic profiling revealed extensive alterations in the cellular metabolome resulting from overexpression of MYCN. Limited supply with either of the two main carbon sources, glucose or glutamine, resulted in distinct shifts in steady-state metabolite levels and significant changes in glutathione metabolism. Interestingly, interference with glutamine-glutamate conversion preferentially blocked proliferation of MYCN overexpressing cells, when glutamine levels were reduced. Thus, our study uncovered MYCN induction and nutrient levels as important metabolic master switches in neuroblastoma cells and identified critical nodes that restrict tumor cell proliferation.

cancer biology↗

bioRxiv2018

5-Hydroxymethylcytosines from Circulating Cell-free DNA as Diagnostic and Prognostic Markers for Hepatocellular Carcinoma

The lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC), the second-most common cause of cancer deaths worldwide. We sought to develop a clinically convenient and minimally-invasive approach that can be deployed at scale for the sensitive, specific, and highly reliable diagnosis of HCC, and to evaluate the potential prognostic value of this approach. The study cohort comprised of 2,728 subjects, including HCC patients (n = 1,208), controls (n = 965) (572 healthy individuals and 393 patients with benign lesions), as well as patients with chronic hepatitis B infection (CHB) (n =291), liver cirrhosis (LC) (n = 110), and cholangiocarcinoma (CCC) (n = 154), was recruited from three major liver cancer hospitals in Shanghai, China, from July 2016 to November 2017. Circulating cell-free DNA (cfDNA) were collected from plasma samples from these individuals before surgery or any radical treatment. Applying our 5hmC-Seal technique, the summarized 5-hydroxymethylcytosine (5hmC) profiles in cfDNA were obtained. Molecular annotation analysis suggested that the profiled 5hmC loci in cfDNA were enriched with liver tissue-derived regulatory markers (e.g., H3K4me1). We showed that a weighted diagnostic score (wd-score) based on 117 genes detected using the summarized 5hmC profiles in cfDNA accurately distinguished HCC patients from controls (AUC = 95.1%; 95% CI, 93.6-96.5%) in the validation set, markedly outperformed -fetoprotein (AFP) with superior sensitivity. The wd-scores, which not only detected early BCLC stages (e.g., Stage 0: AUC = 96.2%; 95% CI,94.1-98.4%) and small tumors (e.g., < 2 cm: AUC = 95.7%; 95% CI: 93.6-97.7%), also showed high capacity for distinguishing HCC from non-cancer patients with CHB/LC (AUC = 80.2%; 95% CI, 75.8-84.6%). Moreover, the prognostic value of 5hmC markers in cfDNA was evaluated for HCC recurrence, showing that a weighted prognostic score (wp-score) based on 16 marker genes predicted the recurrence risk (HR = 6.67; 95% CI, 2.81-15.82, p < 0.0001) in 555 patients who have been followed up after surgery. In conclusion, we have developed and validated a robust 5hmC-based diagnostic model that can be applied routinely with clinically feasible amount of cfDNA (e.g., from ~2-5 mL of plasma). Applying this new approach in the clinic could significantly improve the clinical outcomes of HCC patients, for example by early detection of those patients with surgically resectable tumors or as a convenient disease surveillance tool for recurrence.

cancer biology↗

bioRxiv2018

Tunneling nanotubes contribute to the stroma-mediated imatinib resistance of leukemic cells

Intercellular communication within the bone marrow niche significantly influences leukemogenesis and the sensitivity of leukemic cells to therapy. Tunneling nanotubes (TNTs) are a novel mode of intercellular cross-talk. They are long, thin membranous protrusions that enable the direct transfer of various cargo between cells. Here we show that TNTs are formed between leukemic and bone marrow stromal cells. Fluorescence confocal microscopy with 3D reconstructions, correlative light-electron microscopy and electron tomography provided evidence that TNTs transfer cellular vesicles between cells. The quantitative analysis demonstrated that the stromal cells stimulate TNT-mediated vesicle transfer towards leukemic cells. Transfer of vesicular cargo from stromal cells correlated with increased resistance to anti-leukemic treatment. Moreover, specific sets of proteins with a potential role in survival and the drug response were transferred within these vesicles. Altogether, we found that TNTs are involved in the leukemia-stroma cross-talk and the stroma-mediated cytoprotection of leukemic cells. Our findings implicate TNT connections as a possible target for therapeutic interventions within the leukemia microenvironment to attenuate stroma-conferred protection.

cancer biology↗

bioRxiv2018

Cellular senescence is a central response to cytotoxic chemotherapy in high-grade serous ovarian cancer

High-grade serous ovarian cancer (HGSOC) commonly responds to initial therapy, but this response is rarely durable. Understanding cell fate decisions taken by HGSOC cells in response to treatment could guide new therapeutic opportunities. Here we find that primary HGSOC cultures undergo therapy-induced senescence (TIS) in response to DNA damage induced by chemotherapy. HGSOC-TIS displays most senescence hallmarks including persistent DNA damage, senescence-associated inflammatory secretome, and selective sensitivity to senolytic Bcl-2 family inhibitors, suggesting avenues for preferential synergistic clearance of these cells. Comparison of pre- and post-chemotherapy HGSOC patient tissue samples revealed changes in senescence biomarkers suggestive of post-treatment \"in patient\" TIS, and a stronger TIS response in post-chemotherapy tissues correlated with better 5-year survival rates for patients. Together, these data suggest that the induction of cellular senescence in HGSOC cells accounts at least in part for beneficial cellular responses to treatment in patients providing a new therapeutic target.\n\nOne Sentence SummaryCellular senescence is a central beneficial response to chemotherapy in high-grade serous ovarian cancer both in vitro and in patient.

cancer biology↗

bioRxiv2018

The design, analysis and application of mouse clinical trials in oncology drug development

Mouse clinical trials (MCTs) are becoming widely used in pre-clinical oncology drug development. In this study, we provide some general guidelines on the design, analysis and application of MCTs. We first established empirical quantitative relationships between mouse number and measurement accuracy for both categorical and continuous efficacy endpoints, and showed that more mice are needed to achieve given accuracy for syngeneic models than for PDXs and CDXs. There is considerable disagreement between categorical methods on calling drug responses as objective response, indicating limitations of such approaches. We then introduced linear mixed models, or LMMs, to describe MCTs as clustered longitudinal studies, which explicitly model growth and drug response heterogeneities across mouse models and among mice within a mouse model. Several case studies were used to demonstrate the advantages of LMMs in discovering biomarkers and exploring a drugs mechanism of action. We also introduced the additive frailty models to perform survival analysis on MCTs, which more accurately estimate hazard ratios by modeling the clustered population structures in MCTs. We performed computational simulations for LMMs and frailty models to generate statistical power curves, and showed that statistical power is close for designs with similar total number of mice at given drug efficacy. Finally, we explained how MCTs can explain discrepant results in clinical trials, hence, MCTs are more than preclinical versions of clinical trials but possess their unique values. Results in the report will make MCTs a better tool for oncology drug development.

cancer biology↗

bioRxiv2018

Colloidal quantum dots suitability for long term cell imaging

Fluorescent semiconductor nanoparticles in tree-dimensional quantum confinement, quantum dots (QDs), synthesized in aqueous medium, and functionalized with polyethylene glycol, were used as probes for the long-term imaging of glial cells. In vitro living healthy as well as cancer glial cells were labelled by direct insertion of a small volume of QDs contained in aqueous suspension into the culture wells. A long-term monitoring (over 7 days) of the cells was performed and no evidence of cell fixation and/or damage was observed. Two control groups, healthy and cancer glial cells, were used to compare cell viability. During the observation period, labelled and non labelled cells presented the same dynamics and no difference was observed regarding cell viability. To our knowledge, this is the first report of the viability of hydrophilic prepared quantum dots without any further surface treatment than the polyethylene-glycol coverage for the long-term imaging of living cells. Further, the study also permitted the observation of two distinct interaction mechanisms between cells and QDs. Healthy glial cells were mainly labelled at their surface, while non-healthy glial cells have shown a high rate in the uptake of QDs.

cancer biology↗

bioRxiv2018

Novel 5-Hydroxymethylcytosine Markers for Pancreatic Cancer

OBJECTIVESRobust biomarkers for pancreatic cancer (PaC) early detection/prognosis are critical for improved patient survival. Our goal was to explore the biomarker potential of 5-hydroxymethylcytosines (5hmC), an epigenetic marker with a distinct role in cancer pathobiology, yet under-investigated due largely to technical constraints.\n\nMETHODSWe used the TAB-Array assay, a state-of-the-art technology to directly profile 5hmC at single base resolution with the Illumina EPIC array (>850,000 CpG sites) in 17 pairs of tumor/adjacent tissue samples from US patients.\n\nRESULTSWe demonstrated distinctive distributions of 5hmC in tissues, and substantial differences between tumor and adjacent tissues, suggesting their diagnostic/prognostic value of for PaC.\n\nCONCLUSIONThis study established the potential of 5hmC as a novel epigenetic biomarker for PaC.

cancer biology↗

bioRxiv2018

Molecular changes during extended neoadjuvant letrozole treatment of breast cancer: distinguishing acquired resistance from dormant tumours

BackgroundThe risk of recurrence for endocrine-treated breast cancer patients persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate, previous efforts have been limited to in vitro or in vivo approaches. In this study, sequential tumour samples from patients receiving extended neoadjuvant endocrine treatment were characterised as a novel clinical model.\n\nMethodsConsecutive tumour samples from 62 patients undergoing extended (4-45 months) neoadjuvant aromatase inhibitor, letrozole, therapy were subjected to transcriptomic and proteomic analysis, representing before ([≤]0), early-on (13-120 days) and long-term (>120 days) neoadjuvant letrozole treatment. Patients with at least a 40% initial reduction in tumour size by 4 months of treatment were included. Of these, 42 patients with no subsequent progression were classified as \"dormant\", and the remaining 20 patients as \"acquired resistant\".\n\nResultsChanges in gene expression in dormant tumours begin early and become more pronounced at later timepoints. Therapy-induced changes in resistant tumours were common features of treatment, rather than being specific to resistant phenotype. Comparative analysis of long-term treated dormant and resistant tumours highlighted changes in epigenetics pathways including DNA methylation and histone acetylation. DNA methylation marks 5-methylcytosine and 5-hydroxymethylcytosine were significantly reduced in resistant tumours compared to dormant tissues after extended letrozole treatment.\n\nConclusionsThis is the first patient-matched gene expression study investigating long-term aromatase inhibitor-induced dormancy and acquired resistance in breast cancer. Dormant tumours continue to change during treatment whereas acquired resistant tumours more closely resemble their diagnostic samples. Global loss of DNA methylation was observed in resistant tumours under extended treatment. Epigenetic alterations may lead to escape from dormancy and drive acquired resistance in a subset of patients supporting a potential role for therapy targeted at these epigenetic alterations in the management of endocrine resistant breast cancer.

cancer biology↗

bioRxiv2018

Nuclear export of chimeric mRNAs depends on an lncRNA-triggered autoregulatory loop

Aberrant chromosomal translocations leading to tumorigenesis have been ascribed to the heterogeneously oncogenic functions. However, how fusion transcripts exporting remains to be declared. Here, we showed that the nuclear speckle-specific long non coding RNA MALAT1 controls chimeric mRNA export processes and regulates myeloid progenitor cell differentiation in malignant hematopoiesis. We demonstrated that MALAT1 regulates chimeric mRNAs export in an m6A-dependent manner and thus controls hematopoietic cell differentiation. Specifically, reducing MALAT1 or m6A methyltransferases and the reader YTHDC1 result in the universal retention of distinct oncogenic gene mRNAs in nucleus. Mechanically, MALAT1 hijacks both the chimeric mRNAs and fusion proteins in nuclear speckles during chromosomal translocations and mediates the colocalization of oncogenic fusion proteins with METTL14. MALAT1 and fusion protein complexes serve as a functional loading bridge for the interaction of chimeric mRNA and METTL14. This study demonstrated a universal mechanism of chimeric mRNA transport that involves lncRNA-fusion protein-m6A autoregulatory loop for controlling myeloid cell differentiation. Targeting the lncRNA-triggered autoregulatory loop to disrupt chimeric mRNA transport might represent a new common paradigm for treating blood malignancies.

cancer biology↗

bioRxiv2018

WNT1 Inducible Signaling Pathway Protein 1 (WISP1) Stimulates Melanoma Cell Invasion and Metastasis by Promoting Epithelial - Mesenchymal Transition (EMT)

Besides intrinsic changes, malignant cells release soluble signals to reshape their microenvironment. Among the signaling factors is WNT1 inducible signaling pathway protein 1 (WISP1), a secreted matricellular protein that is elevated in a variety of cancers including melanoma and is associated with reduced overall survival of patients diagnosed with primary melanoma. In this work, we found that WISP1 knockout both increased cell proliferation and repressed wound healing, migration and invasion of mouse and human melanoma cells in an ensemble of in vitro assays. In vivo metastasis assays showed that WISP1 knockout repressed tumor metastasis in both C57BL/6Ncrl and NOD-scid IL2Rgammanull (NSG) mice with B16F10 and YUMM1.7 melanoma cells. Mechanistically, B16F10 cells that invaded in a transwell assay possessed a gene expression signature similar to Epithelial - Mesenchymal Transition (EMT), including coincident repression of E-cadherin and induction of fibronectin and N-cadherin. Upon WISP1 knockout, these EMT signature genes went in opposite directions in both mouse and human cell lines and were rescued by media containing WISP1 or recombinant WISP1 protein. In vivo, metastasis repression by WISP1 knockout was reversed by the reintroduction of either WISP1 or SNAI1. A set of EMT gene activation and inhibition experiments using recombinant WISP1 or kinase inhibitors in B16F10 and YUMM1.7 cells suggested that WISP1 activates Akt and MAP kinase signaling pathways to shift melanoma cells from a proliferative to invasive phenotype. Collectively, the results supported a model that WISP1 within the tumor microenvironment stimulates melanoma invasion and metastasis by promoting an EMT-like process.

cancer biology↗