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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 Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2017

A Bulky Glycocalyx Fosters Metastasis Formation by Promoting G1 Cell Cycle Progression

Metastasis depends upon cancer cell growth and survival within the metastatic niche. Tumors which remodel their glycocalyces, by overexpressing bulky glycoproteins like mucins, exhibit a higher predisposition to metastasize, but the role of mucins in oncogenesis remains poorly understood. Here we report that a bulky glycocalyx promotes the expansion of disseminated tumor cells in vivo by fostering integrin adhesion assembly to permit G1 cell cycle progression. We engineered tumor cells to display glycocalyces of various thicknesses by coating them with synthetic mucin-mimetic glycopolymers. Cells adorned with longer glycopolymers showed increased metastatic potential, enhanced cell cycle progression, and greater levels of integrin-FAK mechanosignaling and Akt signaling in a syngeneic mouse model of metastasis. These effects were mirrored by expression of the ectodomain of cancer-associated mucin MUC1. These findings functionally link mucinous proteins with tumor aggression, and offer a new view of the cancer glycocalyx as a major driver of disease progression.

cancer biology↗

bioRxiv2017

Tracking Subclonal Mutation Frequencies Throughout Lymphomagenesis Identifies Cancer Drivers in Mouse Models of Lymphoma.

Determining whether recurrent but rare cancer mutations are bona fide driver mutations remains a bottleneck in cancer research. Here we present the most comprehensive analysis of retrovirus driven lymphomagenesis produced to date, sequencing 700,000 mutations from >500 malignancies collected at time points throughout tumor development. This enabled identification of positively selected events, and the first demonstration of negative selection of mutations that may be deleterious to tumor development indicating novel avenues for therapy. Customized sequencing and bioinformatics methodologies were developed to quantify subclonal mutations in both premalignant and malignant tissue, greatly expanding the statistical power for identifying driver mutations and yielding a high-resolution, genome wide map of the selective forces surrounding cancer gene loci. Screening two BCL2 transgenic models confirms known drivers of human B-cell non-Hodgkin lymphoma, and implicates novel candidates including modifiers of immunosurveillance such as co-stimulatory molecules and MHC loci. Correlating mutations with genotypic and phenotypic features also gives robust identification of known cancer genes independently of local variance in mutation density. An online resource http://mulv.lms.mrc.ac.uk allows customized queries of the entire dataset.

cancer biology↗

bioRxiv2017

SHP2 Is Required for BCR-ABL1-Induced Hematologic Neoplasms

BCR-ABL1-targeting tyrosine kinase inhibitors (TKIs) have revolutionized treatment of Philadelphia chromosome-positive (Ph+) hematologic neoplasms. Nevertheless, acquired TKI resistance remains a major problem in chronic myeloid leukemia (CML), and TKIs are less effective against Ph+ B-cell acute lymphoblastic leukemia (B-ALL). GAB2, a scaffolding adaptor that binds and activates SHP2, is essential for leukemogenesis by BCR-ABL1, and a GAB2 mutant lacking SHP2 binding cannot mediate leukemogenesis. Using a genetic loss-of-function approach and bone marrow transplantation (BMT) models for CML and BCR-ABL1+ B-ALL, we show that SHP2 is required for BCR-ABL1-evoked myeloid and lymphoid neoplasia. Ptpn11 deletion impairs initiation and maintenance of CML-like myeloproliferative neoplasm, and compromises induction of BCR-ABL1+ B-ALL. SHP2, and specifically, its SH2 domains, PTP activity and C-terminal tyrosines, is essential for BCR-ABL1+, but not WT, pre-B cell proliferation. The MEK/ERK pathway is regulated by SHP2 in WT and BCR-ABL1+ pre-B cells, but is only required for the proliferation of BCR-ABL1+ cells. SHP2 is required for SRC family kinase (SFK) activation only in BCR-ABL1+ pre-B cells. RNAseq reveals distinct SHP2-dependent transcriptional programs in BCR-ABL1+ and WT pre-B cells. Our results suggest that SHP2, via SFKs and ERK, represses MXD3/4 to facilitate a MYC-dependent proliferation program in BCR-ABL1-transformed pre-B cells.

cancer biology↗

bioRxiv2017

Neutral tumor evolution?

Tumor growth is an evolutionary process governed by somatic mutation, clonal selection and random genetic drift, constrained by the co-evolution of the microenvironment1,2. Tumor subclones are subpopulations of tumor cells with a common set of mutations resulting from the expansion of a single cell during tumor development, and have been observed in a significant fraction of cancers and across multiple cancer types3. Peter Nowell proposed that tumors evolve through sequential genetic events4, whereby one cell acquires a selective advantage so that its lineage becomes predominant. According to this traditional model, the selective advantage is conferred by a small set of driver mutations, but, as the subclones that bear them expand successively, they accumulate passenger mutations as well, which can be detected in sequencing experiments1. Genomes of indiv ...

cancer biology↗

bioRxiv2017

Colorectal cancer susceptibility loci as predictive markers of rectal cancer prognosis after surgery

BackgroundColorectal cancer (CRC) is among the leading causes of cancer death. Rectal cancers account for one third of CRC cases. The role and significance of colorectal cancer risk loci in rectal cancer progression has not been investigated.\n\nMethodsWe generated and explored a dataset from 230 rectal cancer patients by gene expression microarray analysis of cancer samples and matched controls, and SNP arrays of germline DNA.\n\nResults8q24 (upstream of MYC) and 18q21 (in the intron of SMAD7), two of the loci most strongly linked with colorectal cancer risk, as well as 20q13 (in the intron of LAMA5), are tightly associated with the prognosis of rectal cancer patients. For SNPs on 18q21 (rs12953717 and rs4464148) and 20q13 (rs4925386), alleles that correlate with higher risk for the development of colorectal cancer are associated with shorter disease free survival. However, for rs6983267 on 8q24, the low risk allele is associated with a higher risk for recurrence and metastasis after surgery, and importantly, is strongly correlated with the resistance of colorectal cancer cell lines to chemoradiotherapy. We also found that although MYC expression is dramatically increased in cancer, patients with higher levels of MYC have a better prognosis. The expression of SMAD7 is weakly correlated with disease free time. Notably, the presence of the 8q24 and 18q21 SNP alleles is not correlated with a change of expression of MYC and SMAD7. rs4464148, and probably rs6983267 and rs4925386, are linked with overall survival time of patients.\n\nConclusionsSNPs at three colorectal cancer risk loci detect subpopulations of rectal cancer patients with poor prognosis. rs6983267 probably affects prognosis through interfering with the resistance of cancer cells to chemoradiotherapy.

cancer biology↗

bioRxiv2017

Transient telomerase inhibition alters cell cycle kinetics

Telomerase is the ribonucleoprotein reverse transcriptase that catalyzes the synthesis of telomeres at the ends of linear human chromosomes and contributes to proper telomere-loop (T-loop) formation. Formation of the T-loop, an obligate step before cell division can proceed, requires the generation of a 3-overhang on the G-rich strand of telomeric DNA via telomerase or C-strand specific nucleases. Here, we discover telomerase activity is critical for efficient cell cycle progression using transient chemical inhibition by the telomerase inhibitor imetelstat. Telomerase inhibition caused changes in cell cycle kinetics and increased the proportion of cells in G2 phase, suggesting delayed clearance through this checkpoint. Investigating the possible contribution of unstructured telomere ends to these cell cycle distribution changes, we observed that imetelstat treatment induced {gamma}H2AX DNA damage foci in a subset of telomerase-positive cells but not telomerase-negative primary human fibroblasts. Chromatin-immunoprecipitation with {gamma}H2AX antibodies demonstrated imetelstat treatment-dependent enrichment of this DNA damage marker at telomeres. Notably, the effects of telomerase inhibition on cell cycle profile alterations were abrogated by pharmacological inhibition of the DNA-damage-repair transducer ATM.\n\nAdditionally, imetelstat potentiation of etoposide, a DNA-damaging drug that acts preferentially during S/G2 phases of the cell cycle, also depended on functional ATM signaling. Our results suggest that telomerase inhibition delays the removal of ATM-dependent DNA damage signals from telomeres in telomerase-positive cancer cells. This demonstrates for the first time that telomerase activity directly facilitates the progression of the cell cycle through modulation of transient telomere dysfunction signals.

cancer biology↗

bioRxiv2017

Kinome rewiring reveals AURKA is a molecular barrier to the efficacy of PI3K/mTOR-pathway inhibitors in breast cancer

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest. We hypothesized that dynamic changes in signaling, including adaptation and feedback, limit drug efficacy. Using a quantitative chemoproteomics approach we mapped dynamic changes in the kinome in response to various agents and identified signaling changes that correlate with drug sensitivity. Measurement of dynamics across a panel of breast cancer cell lines identified that maintenance of CDK4 and AURKA activity was associated with drug resistance. We tested whether incomplete inhibition of CDK4 or AURKA was a source of therapy failure and found that inhibition of either was sufficient to sensitize most breast cancer cells to PI3K, AKT, and mTOR inhibitors. In particular, drug combinations including the AURKA inhibitor MLN8237 were highly synergistic and induced apoptosis through enhanced suppression of mTOR signaling to S6 and 4E-BP1 leading to tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of target therapy and indicates that Aurora kinase co-inhibition could unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer.

cancer biology↗

bioRxiv2017

Ponatinib shows potent antitumor activity in small cell carcinoma of the ovary hypercalcemic type (SCCOHT) through multi-kinase inhibition

Structured AbstractPurpose: Subunits of the SWI/SNF chromatin-remodeling complex are tumor suppressors inactivated in [~]20% of all cancers. Yet, few targeted treatments for SWI/SNF-mutant cancers exist. Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare, aggressive ovarian cancer in young women that is universally driven by loss of the SWI/SNF ATPase subunits, SMARCA4 and SMARCA2. Given poor two-year survival rates for these women, a great need exists for effective targeted therapies.\n\nExperimental Design: To identify underlying therapeutic vulnerabilities in SCCOHT, we conducted high-throughput siRNA and drug screens. Complementary proteomics approaches comprehensively profiled kinases inhibited by ponatinib. Ponatinib was tested for efficacy in two PDX models and one cell line xenograft model of SCCOHT.\n\nResults: FGFRs and PDGFRs were overlapping hits between screens and the receptor tyrosine kinase (RTK) family was enriched in the siRNA screen hits. Evaluation of eleven RTK inhibitors in three SCCOHT cell lines identified ponatinib, an inhibitor of multiple RTKs, as the most effective clinically approved agent. Proteomics approaches confirmed inhibition of known targets of ponatinib and more than 20 non-canonical ponatinib targets. Ponatinib also delayed tumor doubling time 4-fold in SCCOHT-1 xenografts and reducing final tumor volumes in two SCCOHT patient-derived xenograft (PDX) models by 58.6% and 42.5%.\n\nConclusion: Ponatinib is an effective agent for SCCOHT in both in vitro and in vivo preclinical models through its inhibition of multiple kinases. Clinical investigation of this FDA-approved oncology drug in SCCOHT is warranted.\n\nAdditional InformationThis work was supported by research funds from the Canadian Cancer Society Research Institute 34 (#703458, D.G.H.), the National Institutes of Health (R01 CA195670-01, B.E.W., D.G.H., and 35 J.M.T., and T32 HL007106-39 to E.M.C), the Terry Fox Research Institute Initiative New Frontiers Program in Cancer (#1021, D.G.H.), the British Columbia Cancer Foundation (D.G.H.), the VGH & UBC Foundation (D.G.H.), the Anne Rita Monahan Foundation (P.R.), the Marsha Rivkin Center for Ovarian Cancer Research (J.M.T.), the Ovarian Cancer Alliance of Arizona (J.M.T.), the Small Cell Ovarian Cancer Foundation (P.R., J.D.L., B.V., and J.M.T.), and philanthropic support to the TGen Foundation (J.M.T.).\n\nCOI disclosure statement: The authors declare no potential conflicts of interest.

cancer biology↗

bioRxiv2017

Distinctive desmoplastic 3D morphology associated with BRAFV600E in papillary thyroid cancers

Textbooks suggest that cancers are compact balls with an inner core and an invasive front in contact with non-cancerous cells, and that tumor growth is driven by tumor cell proliferation subsequent to oncogenic genome mutations. We reconstructed at histological scale the 3D volume occupied by tumor cells in two regions of a BRAFV600E-mutated papillary thyroid carcinoma (PTC) with low tumor purity, as determined by sequencing, but initially considered high purity during pathology review. In contrast with a compact ball, tumor cells formed a sparse mesh deeply embedded within the stroma. The concepts of inner core and invasive front broke down in this morphology: all tumor cells were within short distance from the stroma. The fibrous stroma was highly cellular and proliferative, a result confirmed in an independent series. This case was not unique: 3.5% of The Cancer Genome Atlas PTCs had purities <25%, 27% were below the 60% purity inclusion criterion. Moreover, the presence of BRAFV600E was associated with extensive fibrosis, high stromal activation, and dedifferentiation. Thus, non-tumor cells make most of the tumor mass and contribute to its expansion in a significant fraction of BRAFV600E PTCs. Therapeutics targeting the tumor-stroma crosstalk could be beneficial in this context.

cancer biology↗

bioRxiv2017

Translational and HIF1α-dependent metabolic reprograming underpin oncometabolomeplasticity and synergy between oncogenic kinase inhibitors and biguanides.

There is heightened interest to devise therapies that target the oncometabolome. We show that kinase inhibitors (KIs) and biguanides synergistically target melanoma, leukemia, and breast, colon and renal cancer cells, but not non-transformed cells. Metabolic profiling confirmed opposing effects of KIs and biguanides on glycolysis, but this was insufficient to explain the observed synergy between the drugs. Rather, we define a critical role for the synthesis of non-essential amino acids (NEAA) aspartate, asparagine and serine as well as reductive glutamine metabolism, in determining the sensitivity of cancer cells to KI - biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine and serine synthesis by modulating translation of mRNAs encoding PC, ASNS, PHGDH and PSAT1. Ablation of 4E-BP1 and 2 results in a dramatic increase in serine, aspartate and asparagine levels and a substantial decrease in sensitivity of breast cancer and melanoma cells to KI - biguanide combinations. In turn, efficacy of KI - biguanide combinations is impeded by HIF1 and sustained reductive glutamine metabolism. These findings identify hitherto unappreciated translational reprograming of NEAA synthesis and HIF1-dependent stimulation of reductive glutamine metabolism as critical metabolic vulnerabilities of cancer that underpin synergy between KIs and biguanides.

cancer biology↗

bioRxiv2017

The evolutionary history of 2,658 cancers

Cancer develops through a process of somatic evolution. Here, we use whole-genome sequencing of 2,778 tumour samples from 2,658 donors to reconstruct the life history, evolution of mutational processes, and driver mutation sequences of 39 cancer types. The early phases of oncogenesis are driven by point mutations in a small set of driver genes, often including biallelic inactivation of tumour suppressors. Early oncogenesis is also characterised by specific copy number gains, such as trisomy 7 in glioblastoma or isochromosome 17q in medulloblastoma. By contrast, increased genomic instability, a nearly four-fold diversification of driver genes, and an acceleration of point mutation processes are features of later stages. Copy-number alterations often occur in mitotic crises leading to simultaneous gains of multiple chromosomal segments. Timing analysis suggests that driver mutations often precede diagnosis by many years, and in some cases decades, providing a window of opportunity for early cancer detection.

cancer biology↗

bioRxiv2017

TumorFusions: an integrative resource for reporting cancer-associated transcript fusions in 33 tumor types

Fusion genes, particularly those involving kinases, have been demonstrated as drivers and are frequent therapeutic targets in cancer1. Here, we describe our results on detecting transcript fusions across 33 cancer types from The Cancer Genome Atlas (TCGA), totaling 9,966 cancer samples and 648 normal samples2. Preprocessing, including read alignment to both genome and transcriptome, and fusion detection were carried out using a uniform pipeline3. To validate the resultant fusions, we also called somatic structural variations for 561 cancers from whole genome sequencing data. A summary of the data used in this study is provided in Table S1. Our results can be accessed per our portal at http://www.tumorfusions.org.

cancer biology↗

bioRxiv2017

Somatic genome editing with the RCAS/TVA-CRISPR/Cas9 system for precision tumor modeling

It has been gradually established that the vast majority of human tumors are extraordinarily heterogeneous at a genetic level. To accurately recapitulate this complexity, it is now evident that in vivo animal models of cancers will require to recreate not just a handful of simple genetic alterations, but possibly dozens and increasingly intricate. Here, we have combined the RCAS/TVA system with the CRISPR/Cas9 genome editing tools for precise modeling of human tumors. We show that somatic deletion in neural stem cells (NSCs) of a variety of known tumor suppressor genes (Trp53, Cdkn2a and Pten), in combination with the expression of an oncogene driver, leads to high-grade glioma formation. Moreover, by simultaneous delivery of pairs of guide RNAs (gRNAs) we generated different gene fusions, either by chromosomal deletion (Bcan-Ntrk1) or by chromosomal translocation (Myb-Qk), and we show that they have transforming potential in vitro and in vivo. Lastly, using homology-directed-repair (HDR), we also produced tumors carrying the Braf V600E mutation, frequently identified in a variety of subtypes of gliomas. In summary, we have developed an extremely powerful and versatile mouse model for in vivo somatic genome editing, that will elicit the generation of more accurate cancer models particularly appropriate for pre-clinical testing.

cancer biology↗

bioRxiv2017

Consensus on Molecular Subtypes of Ovarian Cancer

INTRODUCTIONVarious computational methods for gene expression-based subtyping of high-grade serous (HGS) ovarian cancer have been proposed. This resulted in the identification of molecular subtypes that are based on different datasets and were differentially validated, making it difficult to achieve consensus on which definitions to use in follow-up studies. We assess three major subtype classifiers for their robustness and association to outcome by a meta-analysis of publicly available expression data, and provide a classifier that represents their consensus.\n\nMETHODSWe use a compendium of 15 microarray datasets consisting of 1,774 HGS ovarian tumors to assess 1) concordance between published subtyping algorithms, 2) robustness of those algorithms to re-clustering across datasets, and 3) association of subtypes with overall survival. A consensus classifier is trained on concordantly classified samples, and validated by leave-one-dataset-out validation.\n\nRESULTSEach subtyping classifier identified subsets significantly differing in overall survival, but were not robust to re-fitting in independent datasets and grouped only approximately one third of patients concordantly into four subtypes. We propose a consensus classifier to identify the minority of unambiguously classifiable tumors across multiple gene expression platforms, using a 100-gene signature. The resulting consensus subtypes correlate with patient age, survival, tumor purity, and lymphocyte infiltration.\n\nCONCLUSIONSOur analysis demonstrates that most HGS ovarian cancers are not able to be subtyped. A minority of tumors can be classified and our proposed consensus classifier consolidates and improves on the robustness of three previously proposed subtype classifiers. It provides reliable stratification of patients with HGS ovarian tumors of clearly defined subtype, and will assist in studying the role of polyclonality in the majority of tumors that are not robustly classifiable.

cancer biology↗

bioRxiv2017

Pan-cancer analysis of whole genomes

We report the integrative analysis of more than 2,600 whole cancer genomes and their matching normal tissues across 39 distinct tumour types. By studying whole genomes we have been able to catalogue non-coding cancer driver events, study patterns of structural variation, infer tumour evolution, probe the interactions among variants in the germline genome, the tumour genome and the transcriptome, and derive an understanding of how coding and non-coding variations together contribute to driving individual patient's tumours. This work represents the most comprehensive look at cancer whole genomes to date. NOTE TO READERS: This is an incomplete draft of the marker paper for the Pan-Cancer Analysis of Whole Genomes Project, and is intended to provide the background information for a series of in-depth papers that will be posted to BioRixv during the summer of 2017.

cancer biology↗

bioRxiv2017

DNA 5-Hydroxymethylcytosines from Cell-free Circulating DNA as Diagnostic Biomarkers for Human Cancers

DNA modifications such as 5-methylcytosines (5mC) and 5-hydroxymethylcytosines (5hmC) are epigenetic marks known to affect global gene expression in mammals(1, 2). Given their prevalence in the human genome, close correlation with gene expression, and high chemical stability, these DNA epigenetic marks could serve as ideal biomarkers for cancer diagnosis. Taking advantage of a highly sensitive and selective chemical labeling technology(3), we report here genome-wide 5hmC profiling in circulating cell-free DNA (cfDNA) and in genomic DNA of paired tumor/adjacent tissues collected from a cohort of 90 healthy individuals and 260 patients recently diagnosed with colorectal, gastric, pancreatic, liver, or thyroid cancer. 5hmC was mainly distributed in transcriptionally active regions coincident with open chromatin and permissive histone modifications. Robust cancer-associated 5hmC signatures in cfDNA were identified with specificity for different cancers. 5hmC-based biomarkers of circulating cfDNA demonstrated highly accurate predictive value for patients with colorectal and gastric cancers versus healthy controls, superior to conventional biomarkers, and comparable to 5hmC biomarkers from tissue biopsies. This new strategy could lead to the development of effective blood-based, minimally-invasive cancer diagnosis and prognosis approaches.

cancer biology↗

bioRxiv2017

PIK3CAH1047R-induced paradoxical ERK activation results in resistance to BRAFV600E specific inhibitors in BRAFV600E PIK3CAH1047R double mutant thyroid tumors.

Thyroid carcinomas are the most prevalent endocrine cancers. The BRAFV600E mutation is found in 40% of the papillary type and 25% of the anaplastic type. BRAFV600E inhibitors have shown great success in melanoma but, they have been, to date, less successful in thyroid cancer. About 50% of anaplastic thyroid carcinomas present mutations/amplification of the phosphatidylinositol 3 kinase. Here we propose to investigate if the hyper activation of that pathway could influence the response to BRAFV600E specific inhibitors.\n\nTo test this, we used two mouse models of thyroid cancer. Single mutant (BRAFV600E) mice responded to BRAFV600E-specific inhibition (PLX-4720), while double mutant mice (BRAFV600E; PIK3CAH1047R) showed resistance and even signs of aggravation. This resistance was abrogated by combination with a phosphoinositide 3-kinase inhibitor. At the molecular level, we could show that this resistance was concomitant to a paradoxical activation of the MAP-Kinase pathway, which could be overturned by phosphoinositide 3-kinase inhibition in vivo in our mouse model and in vitro in human double mutant cell lines.\n\nIn conclusion, we reveal a phosphoinositide 3-kinase driven, paradoxical MAP-Kinase pathway activation as mechanism for resistance to BRAFV600E specific inhibitors in a clinically relevant mouse model of thyroid cancer.

cancer biology↗

bioRxiv2017

Questioning the role of selected somatic PIK3C2B mutations in squamous non-small cell lung cancer oncogenesis.

PI3K signaling is frequently dysregulated in NSCLC-SQCC. In contrast to well characterized components of the PI3K signaling network contributing to the formation of SQCC, potential oncogenic effects of alterations in PIK3C2B are poorly understood. Here, a large cohort (n=362) of NSCLC-SQCC was selectively screened for four reported somatic mutations in PIK3C2B via Sanger sequencing. In addition, two mutations leading to an amino acid exchange in the kinase domain (C1181, H1208R) were examined on a functional level for their oncogenic potential.\n\nNone of the mutations were identified in the cohort while well characterized hotspot PIK3CA mutations were observed at the expected frequency. Ultimately, kinase domain mutations in PI3KC2{beta} were found to have no altering effect on downstream signaling. A set of SQCC tumors sequenced by The Cancer Genome Atlas (TCGA) equally indicates a lack of oncogenic potential of the kinase domain mutations or PIK3C2B in general.\n\nTaken together, this study suggests that PIK3C2B might only have a minor role in SQCC oncogenesis.

cancer biology↗