Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 88,832 bioRxiv papers from 380,874 authors.
Most downloaded bioRxiv papers, since beginning of last month
in category cancer biology
3,048 results found. For more information, click each entry to expand.
132 downloads cancer biology
Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine skin cancer that is either associated with the clonal integration of the Merkel cell polyomavirus or with chronic sun exposure. Immunotherapy is initially effective in many patients with metastatic MCC, but the response is rarely durable. MCC lacks actionable mutations that could be utilized for targeted therapies, but epigenetic regulators, which govern cell fate, provide unexplored therapeutic entry points. Here, we performed a pharmacological screen in MCC cells, targeting epigenetic regulators. We discovered that the lysine-specific histone demethylase 1A (LSD1/KDM1A) is required for MCC growth in vitro and in vivo. HMG20B (BRAF35), a poorly characterized subunit of the LSD1-CoREST complex, is also essential for MCC proliferation. LSD1 inhibition in MCC disrupts the LSD1-CoREST complex, directly induces the expression of key regulators of the neuronal lineage and of members of the TGFβ pathway, and activates a gene expression signature corresponding to normal Merkel cells. Our results provide a rationale for evaluating LSD1 inhibitors, which are currently being tested in patients with leukemia and solid tumors, in MCC. ### Competing Interest Statement The authors have declared no competing interest.
131 downloads cancer biology
Ke Cong, Arne Nedergaard Kousholt, Min Peng, Nicholas J Panzarino, Wei Ting Chelsea Lee, Sumeet Nayak, John Krais, Jennifer Calvo, Matt Bere, Eli Rothenberg, Neil Johnson, Jos Jonkers, Sharon B. Cantor
BRCA1 or BRCA2 (BRCA)-deficient tumor cells have defects in DNA double strand break repair by homologous recombination (HR) and fork protection (FP) that are thought to underlie the sensitivity to poly(ADP-ribose) polymerase inhibitor (PARPi). Given the recent finding that PARPi accelerates DNA replication, it was proposed that high speed DNA replication leads to DNA double strand breaks (DSBs). Here, we tested the alternative hypothesis that PARPi sensitivity in BRCA deficient cells results from combined replication dysfunction that causes a lethal accumulation of replication-associated single-stranded DNA (ssDNA) gaps. In support of a gap toxicity threshold, PARPi-induced ssDNA gaps accumulate more excessively in BRCA deficient cells and are suppressed in de novo and genetic models of PARPi resistance while defects in HR or FP often lack this correlation. We also uncouple replication speed from lethality. The clear link between PARPi sensitivity and ssDNA gaps provides a new paradigm for understanding synthetic lethal interactions.
131 downloads cancer biology
Immune checkpoint-inhibitory antibodies (ICIs) are well-established immunotherapies. Despite this, the impact of ICI therapy on non-T cell intratumoral immune cells is ill-defined, restraining the improvement of ICI efficacy. Preclinical murine models of human disease are infrequently validated in clinical trials, impairing the identification of novel biological factors impacting clinical ICI response. To address this barrier, we used our previously described computational approach that integrates high-throughput single-cell RNA sequencing datasets to identify known and novel cellular alterations induced by ICIs that are conserved in mice and humans. We found a signature of intratumoral natural killer (NK) cell activation that is enriched in anti-CTLA-4 treated mouse tumors and correlates with longer overall survival and is predictive of anti-CTLA-4 (ipilimumab) response in melanoma patients. We demonstrate that human NK cells express CTLA-4, which directly binds anti-CTLA-4. These data reveal a novel role for NK cells in anti-CTLA-4 treatment and present opportunities to enhance ICI efficacy. Importantly, we provide a new computational tool for onco-immunology that can identify and validate biological observations across species. ### Competing Interest Statement The authors have declared no competing interest.
130 downloads cancer biology
Purpose: Cyclin dependent kinase 4/6 inhibitors (CDK4/6i) lead to cell-cycle arrest but also demonstrate antineoplastic activity through triggering T cell-mediated immunity. One of the potential mechanisms responsible for this immunological effect might be qualitative and quantitative changes in human leukocyte antigen (HLA) ligands on the cell surface after treatment with CDK4/6i. These changes may increase the immunogenicity of breast cancer cells offering potential synergies for combinations with cancer immunotherapies. Experimental Design: We investigated the ability of two CDK4/6 inhibitors (CDK4/6i), Abemaciclib and Palbociclib, to alter the immunopeptidome at subclinical, non-toxic, levels in different breast cancer cell lines. Biochemical isolation of HLA ligands, identification by mass spectrometry and subsequent network analysis after drug treatment were used to characterize the changes in the immunopeptidome. The mechanisms for altered CDK4/6 presentation were explored. Results: Low-dose treatment with 100nM of Abemaciclib and Palbociclib led to upregulation of cell surface HLA levels and induced hundreds of HLA ligands in breast cancer cell lines. These new ligands were significantly and most strongly enriched for peptides derived from proteins involved in the G1/S phase transition of cell cycle pathway and included among others, HLA ligands from CDK4, CDK6, Cyclin D1 and Cyclin E1. An increase in transcript, protein, and subsequent ubiquitination for Cyclin D1, which could lead to enhanced degradation of the target protein, was identified as a potential mechanism for the altered presentation of peptides. Conclusions: CDK4/6i treatment gave rise to drug-induced antigens through cell cycle disruption and increased antigen presentation. Interestingly, these induced HLA ligands are often sourced from the proteins of the CDK4/CDK6/CCND1 complex or more downstream interaction partners, providing evidence that inhibition of a distinct cellular pathway leads to increased presentation of the proteins involved. These findings suggested CDK4/6i provided a tool for highly selective induction of HLA ligands that may be targeted by T cell-based immunotherapeutics. ### Competing Interest Statement D.A. Scheinberg has potential conflicts of interest, defined by please fill in Journal of interest by ownership in, income from, or research funds from: Pfizer, Sellas Life Sciences, Iovance, Eureka Therapeutics, and Bristol Myers Squibb.
129 downloads cancer biology
Juha Mehtonen, Susanna Teppo, Mari Lahnalampi, Aleksi Kokko, Riina Kaukonen, Laura Oksa, Maria Bouvy-Liivrand, Alena Malyukova, Saara Laukkanen, Petri I. Mäkinen, Samuli Rounioja, Pekka Ruusuvuori, Olle Sangfelt, Riikka Lund, Tapio Lönnberg, Olli Lohi, Merja Heinäniemi
Tight regulatory loops orchestrate commitment to B-cell fate within bone marrow. Genetic lesions in this gene regulatory network underlie the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). The initial genetic hits, including the common translocation that fuses ETV6 and RUNX1 genes, lead to arrested cell differentiation. Here, we aimed to characterize transcription factor activities along the B-lineage differentiation trajectory as a reference to characterize the aberrant cell states present in leukemic bone marrow, and to identify those transcription factors that maintain cancer-specific cell states for more precise therapeutic intervention. We compared normal B-lineage differentiation and in vivo leukemic cell states using single cell RNA-sequencing (scRNA-seq) and several complementary genomics profiles. Based on statistical tools for scRNA-seq, we benchmarked a workflow to resolve transcription factor activities and gene expression distribution changes in healthy bone marrow lymphoid cell states. We compared these to ALL bone marrow at diagnosis and in vivo during chemotherapy, focusing on leukemias carrying the ETV6-RUNX1 fusion. We show that lymphoid cell transcription factor activities uncovered from bone marrow scRNA-seq have high correspondence with independent ATAC- and ChIP-seq data. Using this comprehensive reference for regulatory factors coordinating B-lineage differentiation, our analysis of ETV6-RUNX1-positive ALL cases revealed elevated activity of multiple ETS-transcription factors in leukemic cells states, including the leukemia genome-wide association study hit ELK3. The accompanying gene expression changes associated with natural killer cell inactivation and depletion in the leukemic immune microenvironment. Moreover, our results suggest that the abundance of G1 cell cycle state at diagnosis and lack of differentiation-associated regulatory network changes during induction chemotherapy represent features of chemoresistance. To target the leukemic regulatory program and thereby overcome treatment-resistance, we show that selective inhibitors of ETS-transcription factors could effectively reduce cell viability. Our data provide a detailed picture of the transcription factor activities that characterize both normal B-lineage differentiation and those acquired in leukemic bone marrow and provide a rational basis for new treatment strategies targeting the immune microenvironment and the active regulatory network in leukemia. ### Competing Interest Statement The authors have declared no competing interest.
126 downloads cancer biology
Ali E. Yesilkanal, Dongbo Yang, Payal Tiwari, Alan U. Sabino, Jiyoung Lee, Xiao-He Xie, Siqi Sun, Christopher Dann, Ethan Steinberg, Timothy Stuhlmiller, Casey Frankenberger, Elizabeth Goldsmith, Gary L Johnson, Alexandre F. Ramos, Marsha R. Rosner
Metastasis suppression by high-dose, multi-drug targeting is largely unsuccessful due to network heterogeneity and compensatory network activation. Here we show that targeting driver network signaling capacity by limited inhibition of its core pathways is a more effective anti-metastatic strategy. This principle underlies the action of a physiological metastasis suppressor, Raf Kinase Inhibitory Protein, which moderately decreases stress-regulated MAP kinase network activity, reducing the output to metastatic transcription factor BACH1 and motility-related target genes. We developed a low-dose four-drug mimic that blocks metastatic colonization in mouse breast cancer models and increases survival. Experiments and network flow modeling show: 1) limited inhibition of multiple pathways is required to overcome variation in MAPK network topology and suppress signaling output across heterogeneous tumor cells, and 2) restricting inhibition of individual kinases dissipates surplus signal, preventing threshold activation of compensatory kinase networks. This low-dose multi-drug approach to decrease signaling capacity of driver networks represents a transformative, clinically-relevant strategy for anti-metastatic treatment. ### Competing Interest Statement The authors have declared no competing interest.
124 downloads cancer biology
Gabriel Therizols, Zeina Bash-Imam, Baptiste Panthu, Christelle Machon, Anne Vincent, Sophie Nait-Slimane, Maxime Garcia, Mounira Chalabi-Dchar, Florian Lafôrets, Virginie Marcel, Jihane Boubaker-Vitre, Guillaume Souahlia, Marie-Alexandra Albaret, Hichem C. Mertani, Michel Prudhomme, Martin Bertrand, Jean-Christophe Saurin, Philippe Bouvet, Théophile Ohlmann, Jérôme Guitton, Nicole Dalla-Venezia, Julie Pannequin, Frédéric Catez, Jean-Jacques Diaz
Partial response to chemotherapy leads to disease resurgence. Upon treatment, a subpopulation of cancer cells, called drug-tolerant persistent cells, display a transitory drug tolerance that lead to treatment resistance. Though drug-tolerance mechanisms remain poorly known, they have been linked to non-genomic processes, including epigenetics, stemness and dormancy. 5-fluorouracil (5-FU), the most widely used chemotherapy in cancer treatment, is associated with resistance. While prescribed as an inhibitor of DNA replication, 5-FU alters all RNA pathways. Here, we show that 5-FU treatment leads to the unexpected production of fluorinated ribosomes, exhibiting altered mRNA translation. 5-FU is incorporated into ribosomal RNAs of mature ribosomes in cancer cell lines, colorectal xenografts and human tumours. Fluorinated ribosomes appear to be functional, yet, they display a selective translational activity towards mRNAs according to the nature of their 5'-untranslated region. As a result, we found that sustained translation of IGF-1R mRNA, which codes for one of the most potent cell survival effectors, promoted the survival of 5-FU-treated colorectal cancer cells. Altogether, our results demonstrate that "man-made" fluorinated ribosomes favour the drug-tolerant cellular phenotype by promoting translation of survival genes. This could be exploited for developing novel combined therapies. By unraveling translation regulation as a novel gene expression mechanism helping cells to survive a drug-challenge, our study extends the spectrum of molecular mechanisms driving drug-tolerance. ### Competing Interest Statement The authors have declared no competing interest.
123 downloads cancer biology
Crosstalk between tumor cells and other cells within the tumor microenvironment (TME) plays a crucial role in tumor progression, metastases, and therapy resistance. We present iTALK, a computational approach to characterize and illustrate intercellular communication signals in the multicellular tumor ecosystem using single-cell RNA sequencing data. iTALK can in principle be used to dissect the complexity, diversity, and dynamics of cell-cell communication from a wide range of cellular processes.
123 downloads cancer biology
Fibroblasts are functionally heterogeneous cells, capable of promoting and suppressing tumour progression. Across cancer types, the extent and cause of this phenotypic diversity remains unknown. We used single-cell RNA sequencing and multiplexed immunohistochemistry to examine fibroblast heterogeneity in human lung and non-small cell lung cancer (NSCLC) samples. This identified seven fibroblast subpopulations: including inflammatory fibroblasts and myofibroblasts (representing terminal differentiation states), quiescent fibroblasts, proto-myofibroblasts (x2) and proto-inflammatory fibroblasts (x2). Fibroblast subpopulations were variably distributed throughout tissues but accumulated at discrete niches associated with differentiation status. Bioinformatics analyses suggested TGF-β1 and IL-1 as key regulators of myofibroblastic and inflammatory differentiation respectively. However, in vitro analyses showed that whilst TGF-β1 stimulation in combination with increased tissue tension could induce myofibroblast marker expression, it failed to fully re-capitulate ex-vivo phenotypes. Similarly, IL-1β treatment only induced upregulation of a subset of inflammatory fibroblast marker genes. In silico modelling of ligand-receptor signaling identified additional pathways and cell interactions likely to be involved in fibroblast activation, which can be examined using publicly available R shiny applications. This highlighted a potential role for IL-11 and IL-6 (among other ligands) in myofibroblast and inflammatory fibroblast activation respectively. This analysis provides valuable insight into fibroblast subtypes and differentiation mechanisms in NSCLC. ### Competing Interest Statement The authors have declared no competing interest.
121 downloads cancer biology
Ziad Bakouny, David A. Braun, Sachet A. Shukla, Wenting Pan, Xin Gao, Yue Hou, Abdallah Flaifel, Stephen Tang, Alice Bosma-Moody, Meng Xiao He, Natalie Vokes, Jackson Nyman, Wanling Xie, Amin H. Nassar, Sarah Abou Alaiwi, Ronan Flippot, Gabrielle Bouchard, John A. Steinharter, Pier Vitale Nuzzo, Miriam Ficial, Miriam Sant’Angelo, Juliet Forman, Jacob E. Berchuck, Shaan Dudani, Kevin Bi, Jihye Park, Sabrina Camp, Maura Sticco-Ivins, Laure Hirsch, Megan Wind-Rotolo, Petra Ross-Macdonald, Maxine Sun, Gwo-Shu Mary Lee, Steven L. Chang, Xiao X. Wei, Bradley A. McGregor, Lauren C. Harshman, Giannicola Genovese, Leigh Ellis, Mark Pomerantz, Michelle S. Hirsch, Matthew L Freedman, Michael B. Atkins, Catherine J. Wu, Thai H. Ho, W. Marston Linehan, David F. McDermott, Daniel Y.C. Heng, Srinivas R. Viswanathan, Sabina Signoretti, Eliezer M. Van Allen, Toni K. Choueiri
Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors1−3, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD−L1 expression. Our findings shed light on the molecular drivers of aggressivity and responsiveness to immune checkpoint inhibitors of S/R RCC tumors. ### Competing Interest Statement ZB: reported nonfinancial support from Bristol-Myers Squibb and Genentech/ImCore. D.A.B. reported nonfinancial support from, Bristol-Myers Squibb, and personal fees from Octane Global, Defined Health, Dedham Group, Adept Field Solutions, Slingshot Insights, Blueprint Partnerships, Charles River Associates, Trinity Group, and Insight Strategy, outside of the submitted work. S.A.S. reported nonfinancial support from Bristol-Myers Squibb, and equity in 152 Therapeutics outside the submitted work. X.G: Research Support to Institution: Exelixis. X.X.W: Research Support: BMS. B.A.M is a consultant for Bayer, Astellas, Astra Zeneca, Seattle Genetics, Exelixis, Nektar, Pfizer, Janssen, Genentech and EMD Serono. He received research support to Dana Farber Cancer Institute (DFCI) from Bristol Myers Squibb, Calithera, Exelixis, Seattle Genetics. L.C.H reports consulting fees from Genentech, Dendreon, Pfizer, Medivation/Astellas, Exelixis, Bayer, Kew Group, Corvus, Merck, Novartis, Michael J Hennessy Associates (Healthcare Communications Company and several brands such as OncLive and PER), Jounce, EMD Serrano, and Ology Medical Education; Research funding from Bayer, Sotio, Bristol-Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer, Endocyte (Novartis), and support for research travel from Bayer and Genentech. M.B.A: Advisory Board participation: BMS, Merck, Novartis, Arrowhead, Pfizer, Galactone, Werewolf, Fathom, Pneuma, Leads BioPharma; Consultant: BMS, Merck, Novartis, Pfizer, Genentech-Roche, Exelixis, Eisai, Aveo, Array, AstraZeneca, Ideera, Aduro, ImmunoCore, Boehringer-Ingelheim, Iovance, Newlink, Pharma, Surface, Alexion, Acceleron, Cota, Amgen; Research Support to institution: BMS, Merck, Pfizer, Genentech. C.J.W: Co-founder of Neon Therapeutics, and is a member of its SAB. Receives research funding from Pharmacyclics. T.H.H: Advisory board participation: Surface Therapeutics, Exelixis, Genentech, Pfizer, Ipsen, Cardinal Health; research support-Novartis. D.F.M reports a consulting/advisory role for Bristol-Myers Squibb, Merck, Roche/Genentech, Pfizer, Exelixis, Novartis, Eisai, X4 Pharmaceuticals, and Array BioPharma; and reports that his home institution receives research funding from Prometheus Laboratories. D.H: consulting or research funding from Pfizer, Novartis, BMS, Ipsen, Exelixis, and Merck. S.S: Research support to Institution: Bristol-Myers Squibb, AstraZeneca, Novartis, Exelixis; Consultant: Merck, AstraZeneca, Bristol-Myers Squibb, AACR, and NCI; royalties: Biogenex. E.M.V: Advisory/Consulting: Tango Therapeutics, Genome Medical, Invitae, Illumina, Ervaxx; Research support: Novartis, BMS; Equity: Tango Therapeutics, Genome Medical, Syapse, Ervaxx, Microsoft; Travel reimbursement: Roche/Genentech; Patents: Institutional patents filed on ERCC2 mutations and chemotherapy response, chromatin mutations and immunotherapy response, and methods for clinical interpretation. T.K.C: Research (Institutional and personal): AstraZeneca, Alexion, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Ipsen, Tracon, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Lilly, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Calithera, Analysis Group, Sanofi/Aventis, Takeda, National Cancer Institute (NCI), National Institute of Health (NIH), Department of Defense (DOD).; Honoraria: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, Roche Products Limited, F. Hoffmann-La Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, NCCN, Michael J. Hennessy (MJH) Associates, Inc (Healthcare Communications Company with several brands such as OnClive, PeerView and PER), Research to Practice, L-path, Kidney Cancer Journal, Clinical Care Options, Platform Q, Navinata Healthcare, Harborside Press, American Society of Medical Oncology, NEJM, Lancet Oncology, Heron Therapeutics, Lilly, ASCO, ESMO ; Consulting or Advisory Role: AstraZeneca, Alexion, Sanofi/Aventis, Bayer, Bristol Myers-Squibb/ER Squibb and sons LLC, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Heron Therapeutics, Lilly, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, EMD Serono, Prometheus Labs, Corvus, Ipsen, Up-to-Date, NCCN, Analysis Group, Pionyr, Tempest.; No speaker bureau; Stock ownership: Pionyr, Tempest.; No leadership or employment in for-profit companies. Other present or past leadership roles: Director of GU Oncology Division at Dana-Farber and past President of medical Staff at Dana-Farber), member of NCCN Kidney panel and the GU Steering Committee, past chairman of the Kidney Cancer Association Medical and Scientific Steering Committee); Patents, royalties or other intellectual properties: International Patent Application No. PCT/US2018/12209, entitled PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response, filed January 3, 2018, claiming priority to U.S. Provisional Patent Application No. 62/445,094, filed January 11, 2017 and International Patent Application No. PCT/US2018/058430, entitled Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, filed October 31, 2018, claiming priority to U.S. Provisional Patent Application No. 62/581,175, filed November 3, 2017; Travel, accommodations, expenses, in relation to consulting, advisory roles, or honoraria; Medical writing and editorial assistance support may have been funded by Communications companies funded by pharmaceutical companies (ClinicalThinking, Envision Pharma Group, Fishawack Group of Companies, Health Interactions, Parexel, Oxford PharmaGenesis, and others); The institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter; CV provided upon request for scope of clinical practice and research; Mentored several non-US citizens on research projects with potential funding (in part) from non-US sources/Foreign Components: Asmar Wood S.A.L. is a private company based in Beirut, Lebanon that will provide a total of $100,000 in salary support to Dr. Sarah Abou Alaiwi from 7/1/2018 to 7/1/2020 during her post-doctoral research fellowship at DFCI; Fondation Arc Pour La Recherche Sur Le Cancer is a not-for-profit foundation based in Villejuif, France that provides 2561.04 Euros per month in salary support to Dr. Ronan Flippot during his clinical training at DFCI from 5/2/2018 to 11/4/2018. The other authors declare no potential conflicts of interest.
120 downloads cancer biology
Current evidence indicates that resistance to HER2-targeted therapies is frequently associated with HER3 and active signaling via HER2-HER3 dimers, particularly in the context of breast cancer. Thus, understanding the response to HER2-HER3 signaling and the regulation of the dimer per se remains essential to decipher therapy relapse mechanisms. Here, we demonstrate that signaling by HER3 growth factor ligands, heregulins, support the transcription of a type-1 transmembrane sorting receptor, sortilin-related receptor (SorLA; SORL1) downstream of the mitogen-activated protein kinase pathway. In addition, we demonstrate that SorLA interacts directly with HER3, forming a trimeric complex with HER2 and HER3 to attenuate lysosomal degradation of the dimer through a Rab4-dependent manner. In line with a role for SorLA in supporting the stability of the HER2 and HER3 receptors, loss of SorLA compromised heregulin-induced cell proliferation and sensitized metastatic anti-HER2 therapy-resistant breast cancer cells to neratinib in cancer spheroids in vitro and in vivo in a zebrafish brain xenograft model. Collectively, our results demonstrate a novel feed-forward loop consisting of heregulin, HER2-HER3 and SorLA, which controls breast cancer growth and anti-HER2 therapy resistance in vitro and in vivo. ### Competing Interest Statement The authors have declared no competing interest.
120 downloads cancer biology
Tamara Ouspenskaia, Travis Law, Karl R. Clauser, Susan Klaeger, Siranush Sarkizova, François Aguet, Bo Li, Elena Christian, Binyamin A. Knisbacher, Phuong M. Le, Christina R. Hartigan, Hasmik Keshishian, Annie Apffel, Giacomo Oliveira, Wandi Zhang, Yuen Ting Chow, Zhe Ji, Irwin Jungreis, Sachet A. Shukla, Pavan Bachireddy, Manolis Kellis, Gad A. Getz, Nir Hacohen, Derin B. Keskin, Steven A. Carr, Catherine J. Wu, Aviv Regev
Tumor epitopes – peptides that are presented on surface-bound MHC I proteins - provide targets for cancer immunotherapy and have been identified extensively in the annotated protein-coding regions of the genome. Motivated by the recent discovery of translated novel unannotated open reading frames (nuORFs) using ribosome profiling (Ribo-seq), we hypothesized that cancer-associated processes could generate nuORFs that can serve as a new source of tumor antigens that harbor somatic mutations or show tumor-specific expression. To identify cancer-specific nuORFs, we generated Ribo-seq profiles for 29 malignant and healthy samples, developed a sensitive analytic approach for hierarchical ORF prediction, and constructed a high-confidence database of translated nuORFs across tissues. Peptides from 3,555 unique translated nuORFs were presented on MHC I, based on analysis of an extensive dataset of MHC I-bound peptides detected by mass spectrometry, with >20-fold more nuORF peptides detected in the MHC I immunopeptidomes compared to whole proteomes. We further detected somatic mutations in nuORFs of cancer samples and identified nuORFs with tumor-specific translation in melanoma, chronic lymphocytic leukemia and glioblastoma. NuORFs thus expand the pool of MHC I-presented, tumor-specific peptides, targetable by immunotherapies.
118 downloads cancer biology
Early cancer detection aims to find tumors before they progress to an incurable stage. We developed a stochastic mathematical model of tumor evolution and circulating tumor DNA (ctDNA) shedding to determine the potential and the limitations of cancer early detection tests. We inferred normalized ctDNA shedding rates from 176 early stage lung cancer subjects and calculated that a 15 mL blood sample contains on average 1.7 genome equivalents of ctDNA for lung tumors with a volume of 1 cm3. For annual screening, the model predicts median detection sizes between 3.8 and 6.6 cm3 corresponding to lead times between 310 and 450 days compared to current lung tumor sizes at diagnosis. For monthly cancer relapse testing based on 20 a priori known mutations, the model predicts a median detection size of 0.26 cm3 corresponding to a lead time of 150 days. This mechanistic framework can help to optimize early cancer detection approaches. ### Competing Interest Statement S.A., J.J.C., E.J.M., S.S.H., S.S.G., and J.G.R. declare no competing interests. D.M.K. is a consultant for Roche Molecular Diagnostics. A.A.A. and M.D. are coinventors on patent applications related to CAPP-Seq. A.A.A. has equity in Forty Seven and CiberMed and has served as a consultant for Roche, Genentech, Chugai Pharma and Pharmacyclics. M.D. has equity in CiberMed, has received research funding from Varian Medical Systems and has served as a paid consultant for Roche, AstraZeneca, BioNTech, Illumina and RefleXion and as an unpaid consultant for Genentech.
118 downloads cancer biology
Christian Dubiella, Benika J. Pinch, Daniel Zaidman, Theresa D Manz, Evon Poon, Shuning He, Efrat Resnick, Ellen M. Langer, Colin J. Daniel, Hyuk-Soo Seo, Ying Chen, Scott B. Ficarro, Yann Jamin, Xiaolan Lian, Shin Kibe, Shingo Kozono, Kazuhiro Koikawa, Zainab M. Doctor, Behnam Nabet, Christopher M. Browne, Annan Yang, Liat Stoler-Barak, Richa B. Shah, Nick E. Vangos, Ezekiel A Geffken, Roni Oren, Samuel Sidi, Ziv Shulman, Chu Wang, Jarrod A. Marto, Sirano Dhe-Paganon, Thomas Look, Xiao Zhen Zhou, Kun Ping Lu, Rosalie C Sears, Louis Chesler, Nathanael S. Gray, Nir London
The peptidyl-prolyl cis-trans isomerase, Pin1, acts as a unified signaling hub that is exploited in cancer to activate oncogenes and inactivate tumor suppressors, in particular through up-regulation of c-Myc target genes. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to discover covalent inhibitors targeting Pin1's active site nucleophile - Cys113, leading to the development of Sulfopin, a double-digit nanomolar Pin1 inhibitor. Sulfopin is highly selective for Pin1, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement, and phenocopies genetic knockout of Pin1. Although Pin1 inhibition had a modest effect on viability in cancer cell cultures, Sulfopin induced downregulation of c-Myc target genes and reduced tumor initiation and tumor progression in murine and zebrafish models of MYCN-driven neuroblastoma. Our results suggest that Sulfopin is a suitable chemical probe for assessing Pin1-dependent pharmacology in cells and in vivo. Moreover, these studies indicate that Pin1 should be further investigated as a potential cancer target.
118 downloads cancer biology
Supratentorial ependymoma (ST-EPN) is a type of malignant brain tumor mainly seen in children. Since 2014, it has been known that an intrachromosomal fusion C11orf95-RELA is an oncogenic driver in ST-EPN1 but the molecular mechanisms of oncogenesis are unclear. Here we show that the C11orf95 component of the fusion protein dictates DNA binding activity while the RELA component is required for driving the expression of ependymoma- associated genes. Epigenomic characterizations using ChIP-seq and HiChIP approaches reveal that C11orf95-RELA modulates chromatin states and mediates chromatin interactions, leading to transcriptional reprogramming in ependymoma cells. Our findings provide important characterization of the molecular underpinning of C11orf95- RELA fusion and shed light on potential therapeutic targets for C11orf95-RELA subtype ependymoma. ### Competing Interest Statement The authors have declared no competing interest.
117 downloads cancer biology
Junbin Qian, Siel Olbrecht, Bram Boeckx, Hanne Vos, Damya Laoui, Emre Etlioglu, Els Wauters, Valentina Pomella, Sara Verbandt, Pieter Busschaert, Ayse Bassez, Amelie Franken, Marlies Vanden Bempt, Jieyi Xiong, Birgit Weynand, Yannick van Herck, Asier Antoranz, Francesca Maria Bosisio, Bernard Thienpont, Giuseppe Floris, Ignace Vergote, Ann Smeets, Sabine Tejpar, Diether Lambrechts
The stromal compartment of the tumour microenvironment consists of a heterogeneous set of tissue-resident and tumour-infiltrating cells, which are profoundly moulded by cancer cells. An outstanding question is to what extent this heterogeneity is similar between cancers affecting different organs. Here, we profile 233,591 single cells from patients with lung, colorectal, ovary and breast cancer (n=36) and construct a pan-cancer blueprint of stromal cell heterogeneity using different single-cell RNA and protein-based technologies. We identify 68 stromal cell populations, of which 46 are shared between cancer types and 22 are unique. We also characterise each population phenotypically by highlighting its marker genes, transcription factors, metabolic activities and tissue-specific expression differences. Resident cell types are characterised by substantial tissue specificity, while tumour-infiltrating cell types are largely shared across cancer types. Finally, by applying the blueprint to melanoma tumours treated with checkpoint immunotherapy and identifying a naive CD4+ T-cell phenotype predictive of response to checkpoint immunotherapy, we illustrate how it can serve as a guide to interpret scRNA-seq data. In conclusion, by providing a comprehensive blueprint through an interactive web server, we generate a first panoramic view on the shared complexity of stromal cells in different cancers.
117 downloads cancer biology
The WNT pathway is a fundamental regulator of intestinal homeostasis and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer (CRC). To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that while WNT suppression blocks tumor growth in most organoid and in vivo CRC models, the accumulation of CRC-associated genetic alterations enables drug resistance and WNT-independent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of p53 and SMAD4, transient TGFβ exposure drives YAP/TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work delineates genetic and microenvironmental factors that drive WNT inhibitor resistance, identifies a new mechanism for WNT-independent CRC growth and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs.
117 downloads cancer biology
Konstantin Helmsauer, Maria Valieva, Salaheddine Ali, Rocio Chamorro Gonzalez, Robert Schöpflin, Claudia Röefzaad, Yi Bei, Heathcliff Dorado Garcia, Elias Rodriguez-Fos, Montserrat Puiggròs, Katharina Kasack, Kerstin Haase, Luis P. Kuschel, Philipp Euskirchen, Verena Heinrich, Michael Robson, Carolina Rosswog, Jörn Tödling, Annabell Szymansky, Falk Hertwig, Matthias Fischer, David Torrents, Angelika Eggert, Johannes H Schulte, Stefan Mundlos, Anton G Henssen, Richard P. Koche
MYCN amplification drives one in six cases of neuroblastoma. The supernumerary gene copies are commonly found on highly rearranged, extrachromosomal circular DNA. The exact amplicon structure has not been described thus far and the functional relevance of its rearrangements is unknown. Here, we analyzed the MYCN amplicon structure and its chromatin landscape. This revealed two distinct classes of amplicons which explain the regulatory requirements for MYCN overexpression. The first class always co-amplified a proximal enhancer driven by the noradrenergic core regulatory circuit (CRC). The second class of MYCN amplicons was characterized by high structural complexity, lacked key local enhancers, and instead contained distal chromosomal fragments, which harbored CRC-driven enhancers. Thus, ectopic enhancer hijacking can compensate for the loss of local gene regulatory elements and explains a large component of the structural diversity observed in MYCN amplification.
114 downloads cancer biology
Korsuk Sirinukunwattana, Enric Domingo, Susan Richman, Keara L Redmond, Andrew Blake, Clare Verrill, Simon J Leedham, Aikaterini Chatzipli, Claire Hardy, Celina Whalley, Chieh-Hsi Wu, Andrew D Beggs, Ultan McDermott, Philip Dunne, Angela A Meade, Steven M Walker, Graeme I Murray, Leslie M Samuel, Matthew Seymour, Ian Tomlinson, Philip Quirke, Tim Maughan, Jens Rittscher, Viktor H Koelzer, on behalf of S:CORT consortium
Image analysis is a cost-effective tool to associate complex features of tissue organisation with molecular and outcome data. Here we predict consensus molecular subtypes (CMS) of colorectal cancer (CRC) from standard H&E sections using deep learning. Domain adversarial training of a neural classification network was performed using 1,553 tissue sections with comprehensive multi-omic data from three independent datasets. Image-based consensus molecular subtyping (imCMS) accurately classified CRC whole-slide images and preoperative biopsies, spatially resolved intratumoural heterogeneity and provided accurate secondary calls with higher discriminatory power than bioinformatic prediction. In all three cohorts imCMS established sensible classification in CMS unclassified samples, reproduced expected correlations with (epi)genomic alterations and effectively stratified patients into prognostic subgroups. Leveraging artificial intelligence for the development of novel biomarkers extracted from histological slides with molecular and biological interpretability has remarkable potential for clinical translation.
113 downloads cancer biology
Identifying the complete repertoire of genes that drive cancer in individual patients is crucial for precision oncology. Established methods for driver detection focus mostly on genes that are recurrently altered across cohorts of cancer patients. However, mapping these genes back to patients leaves a sizeable fraction with few or no driver events, hindering our understanding of cancer mechanisms and limiting the choice of therapeutic interventions. Here we present sysSVM2, a tool based on machine learning that integrates somatic alteration data with systems-level gene properties to predict drivers in individual patients. We develop sysSVM2 for pan- cancer applicability, demonstrating robust performance on real and simulated cancer data. We benchmark its performance against other driver detection methods and show that sysSVM2 has a lower false positive rate and superior patient driver coverage. Applying sysSVM2 to 7,646 samples from 34 cancer types, we find that predicted drivers are often rare or patient-specific. However, they converge to disrupt well-known cancer-related processes including DNA repair, chromatin organisation and the cell cycle. sysSVM2 is a resource to enhance personalised predictions of cancer driver events with possible use in research and clinical settings. Code to implement sysSVM2 and the trained models in simulated cancer-agnostic data as well as in 34 cancer types are available at https://github.com/ciccalab/sysSVM2. ### Competing Interest Statement The authors have declared no competing interest.
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