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Grant Details

Grant Number: 5R01CA226802-03 Interpret this number
Primary Investigator: Salomonis, Nathan
Organization: Cincinnati Childrens Hosp Med Ctr
Project Title: Unbiased Identification of Spliceosome Vulnerabilities Across Cancer
Fiscal Year: 2020


Abstract

PROJECT SUMMARY: Although alternative splicing is one of the major drivers of cellular diversity and growth during development, the splicing machinery can be hijacked in cancer to promote metastasis, immune escape, invasion and anti- apoptotic actions. While splicing factor mutations occur in 1-15% of patients, depending on the cancer, emerging data suggest that commonly dysregulated oncogenes such as MYC indirectly regulate mRNA processing pathways leading to cancer promoting alternative splice isoforms in distinct malignancies. Using a series of recently developed unsupervised splicing detection and candidate splicing regulatory prediction techniques, we discovered that splicing is broadly disrupted in adult and pediatric cancers independent of obvious splicing factor mutations. These data suggest a potentially paradigm shifting model, in which widespread coordinated splicing dysfunction occurs across cancers, likely via imbalances in splicing factor expression, signaling or genetic alternations. If true, spliceosome directed and upstream therapies may be broadly repurposed across cancers, focused on specific splicing signatures and implicated regulatory pathways rather than on specific mutations alone. To test these hypotheses and develop reusable analytical resources for the cancer community, we propose the following aims. Aim 1: Implicate key splicing pathway vulnerabilities with observed oncogenic events across diverse cancers. We will characterize alternative splicing on a global-level with our existing integrative multi- omics computational workflow across dozens of cancers and thousands of samples. Splicing events identified using novel unsupervised or supervised analyses will be compared within and between distinct cancers as well as normal cells of different origins to define reproducible tumor intrinsic vs. differentiation associated programs. Aim 2: Define and validate the core splicing regulatory networks in pediatric AML and diverse human cancers. We will build and validate a novel learning model to define the splicing regulatory network in pediatric AML and ultimately across diverse adult and pediatric cancers. We will adapt current best practices for multi-evidence transcriptional regulatory network inference to splicing and rigorously test our models with validation data. A large library of experimental splicing factor binding datasets will be used to improve our predictions. These analyses will identify novel splicing regulators and RNA recognition elements. Aim 3: Build a discovery platform for precision splicing biomarker detection and selective splicing target inhibition. We will develop an interactive computational interface to identify specific RNA isoforms associated with poor prognosis splicing subtypes in diverse cancers obtained in Aim 1. By integrating splicing, gene expression, proteomics and methylation data on the same patients, we will enable the discovery of splicing events linked to diverse modes of gene regulation, that potentially manifest at the protein level. Associated isoform interactions and weighted coexpression networks will be built to prioritize specific splicing events in known cancer pathways.



Publications

Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms.
Authors: Lambourne L. , Mattioli K. , Santoso C. , Sheynkman G. , Inukai S. , Kaundal B. , Berenson A. , Spirohn-Fitzgerald K. , Bhattacharjee A. , Rothman E. , et al. .
Source: Biorxiv : The Preprint Server For Biology, 2024-04-10 00:00:00.0; , .
EPub date: 2024-04-10 00:00:00.0.
PMID: 38617209
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Broad de-regulated U2AF1 splicing is prognostic and augments leukemic transformation via protein arginine methyltransferase activation.
Authors: Venkatasubramanian M. , Schwartz L. , Ramachandra N. , Bennett J. , Subramanian K.R. , Chen X. , Gordon-Mitchell S. , Fromowitz A. , Pradhan K. , Shechter D. , et al. .
Source: Biorxiv : The Preprint Server For Biology, 2024-02-08 00:00:00.0; , .
EPub date: 2024-02-08 00:00:00.0.
PMID: 38370617
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Splicing neoantigen discovery with SNAF reveals shared targets for cancer immunotherapy.
Authors: Li G. , Mahajan S. , Ma S. , Jeffery E.D. , Zhang X. , Bhattacharjee A. , Venkatasubramanian M. , Weirauch M.T. , Miraldi E.R. , Grimes H.L. , et al. .
Source: Science Translational Medicine, 2024-01-17 00:00:00.0; 16(730), p. eade2886.
EPub date: 2024-01-17 00:00:00.0.
PMID: 38232136
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After the Infection: A Survey of Pathogens and Non-communicable Human Disease.
Authors: Lape M. , Schnell D. , Parameswaran S. , Ernst K. , Salomonis N. , Martin L.J. , Harnett B.M. , Kottyan L.C. , Weirauch M.T. .
Source: Medrxiv : The Preprint Server For Health Sciences, 2023-09-14 00:00:00.0; , .
EPub date: 2023-09-14 00:00:00.0.
PMID: 37745430
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Quantifying tumor specificity using Bayesian probabilistic modeling for drug target discovery and prioritization.
Authors: Li G. , Bhattacharjee A. , Salomonis N. .
Source: Biorxiv : The Preprint Server For Biology, 2023-03-06 00:00:00.0; , .
EPub date: 2023-03-06 00:00:00.0.
PMID: 36945433
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The balance between protective and pathogenic immune responses to pneumonia in the neonatal lung is enforced by gut microbiota.
Authors: Stevens J. , Steinmeyer S. , Bonfield M. , Peterson L. , Wang T. , Gray J. , Lewkowich I. , Xu Y. , Du Y. , Guo M. , et al. .
Source: Science Translational Medicine, 2022-06-15 00:00:00.0; 14(649), p. eabl3981.
EPub date: 2022-06-15 00:00:00.0.
PMID: 35704600
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LAMP-5 is an essential inflammatory-signaling regulator and novel immunotherapy target for mixed lineage leukemia-rearranged acute leukemia.
Authors: Gracia-Maldonado G. , Clark J. , Burwinkel M. , Greenslade B. , Wunderlich M. , Salomonis N. , Leone D. , Gatti E. , Pierre P. , Kumar A.R. , et al. .
Source: Haematologica, 2022-04-01 00:00:00.0; 107(4), p. 803-815.
EPub date: 2022-04-01 00:00:00.0.
PMID: 33910331
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DeepImmuno: deep learning-empowered prediction and generation of immunogenic peptides for T-cell immunity.
Authors: Li G. , Iyer B. , Prasath V.B.S. , Ni Y. , Salomonis N. .
Source: Briefings In Bioinformatics, 2021-05-03 00:00:00.0; , .
EPub date: 2021-05-03 00:00:00.0.
PMID: 34009266
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Cannabidiol Treatment Results in a Common Gene Expression Response Across Aggressive Cancer Cells from Various Origins.
Authors: Desprez P.Y. , Murase R. , Limbad C. , Woo R.W.L. , Adrados I. , Weitenthaler K. , Soroceanu L. , Salomonis N. , McAllister S.D. .
Source: Cannabis And Cannabinoid Research, 2021 Apr; 6(2), p. 148-155.
EPub date: 2021-04-15 00:00:00.0.
PMID: 33912679
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DeepImmuno: Deep learning-empowered prediction and generation of immunogenic peptides for T cell immunity.
Authors: Li G. , Iyer B. , Prasath V.B.S. , Ni Y. , Salomonis N. .
Source: Biorxiv : The Preprint Server For Biology, 2020-12-24 00:00:00.0; , .
EPub date: 2020-12-24 00:00:00.0.
PMID: 33398286
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MBNL1 regulates essential alternative RNA splicing patterns in MLL-rearranged leukemia.
Authors: Itskovich S.S. , Gurunathan A. , Clark J. , Burwinkel M. , Wunderlich M. , Berger M.R. , Kulkarni A. , Chetal K. , Venkatasubramanian M. , Salomonis N. , et al. .
Source: Nature Communications, 2020-05-12 00:00:00.0; 11(1), p. 2369.
EPub date: 2020-05-12 00:00:00.0.
PMID: 32398749
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PHIP drives glioblastoma motility and invasion by regulating the focal adhesion complex.
Authors: de Semir D. , Bezrookove V. , Nosrati M. , Scanlon K.R. , Singer E. , Judkins J. , Rieken C. , Wu C. , Shen J. , Schmudermayer C. , et al. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2020-04-21 00:00:00.0; 117(16), p. 9064-9073.
EPub date: 2020-04-09 00:00:00.0.
PMID: 32273388
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Resolving single-cell heterogeneity from hundreds of thousands of cells through sequential hybrid clustering and NMF.
Authors: Venkatasubramanian M. , Chetal K. , Schnell D. , Atluri G. , Salomonis N. .
Source: Bioinformatics (oxford, England), 2020-03-24 00:00:00.0; , .
EPub date: 2020-03-24 00:00:00.0.
PMID: 32207533
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cellHarmony: cell-level matching and holistic comparison of single-cell transcriptomes.
Authors: DePasquale E.A.K. , Schnell D. , Dexheimer P. , Ferchen K. , Hay S. , Chetal K. , Valiente-Alandí Í. , Blaxall B.C. , Grimes H.L. , Salomonis N. .
Source: Nucleic Acids Research, 2019-12-02 00:00:00.0; 47(21), p. e138.
PMID: 31529053
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Aging Human Hematopoietic Stem Cells Manifest Profound Epigenetic Reprogramming of Enhancers That May Predispose to Leukemia.
Authors: Adelman E.R. , Huang H.T. , Roisman A. , Olsson A. , Colaprico A. , Qin T. , Lindsley R.C. , Bejar R. , Salomonis N. , Grimes H.L. , et al. .
Source: Cancer Discovery, 2019 08; 9(8), p. 1080-1101.
EPub date: 2019-05-13 00:00:00.0.
PMID: 31085557
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U2AF1 mutations induce oncogenic IRAK4 isoforms and activate innate immune pathways in myeloid malignancies.
Authors: Smith M.A. , Choudhary G.S. , Pellagatti A. , Choi K. , Bolanos L.C. , Bhagat T.D. , Gordon-Mitchell S. , Von Ahrens D. , Pradhan K. , Steeples V. , et al. .
Source: Nature Cell Biology, 2019 May; 21(5), p. 640-650.
EPub date: 2019-04-22 00:00:00.0.
PMID: 31011167
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Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice.
Authors: Fletcher J.S. , Wu J. , Jessen W.J. , Pundavela J. , Miller J.A. , Dombi E. , Kim M.O. , Rizvi T.A. , Chetal K. , Salomonis N. , et al. .
Source: Jci Insight, 2019-02-07 00:00:00.0; 4(3), .
EPub date: 2019-02-07 00:00:00.0.
PMID: 30728335
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Tissues Harvested Using an Automated Surgical Approach Confirm Molecular Heterogeneity of Glioblastoma and Enhance Specimen's Translational Research Value.
Authors: Zusman E. , Sidorov M. , Ayala A. , Chang J. , Singer E. , Chen M. , Desprez P.Y. , McAllister S. , Salomonis N. , Chetal K. , et al. .
Source: Frontiers In Oncology, 2019; 9, p. 1119.
EPub date: 2019-10-23 00:00:00.0.
PMID: 31750239
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The Human Cell Atlas bone marrow single-cell interactive web portal.
Authors: Hay S.B. , Ferchen K. , Chetal K. , Grimes H.L. , Salomonis N. .
Source: Experimental Hematology, 2018 12; 68, p. 51-61.
EPub date: 2018-09-21 00:00:00.0.
PMID: 30243574
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controls MDS-associated chronic TGF-β signaling, aberrant splicing, and stem cell fitness.
Authors: Muench D.E. , Ferchen K. , Velu C.S. , Pradhan K. , Chetal K. , Chen X. , Weirauch M.T. , Colmenares C. , Verma A. , Salomonis N. , et al. .
Source: Blood, 2018-11-22 00:00:00.0; 132(21), p. e24-e34.
EPub date: 2018-09-24 00:00:00.0.
PMID: 30249787
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Defective transcription elongation in a subset of cancers confers immunotherapy resistance.
Authors: Modur V. , Singh N. , Mohanty V. , Chung E. , Muhammad B. , Choi K. , Chen X. , Chetal K. , Ratner N. , Salomonis N. , et al. .
Source: Nature Communications, 2018-10-23 00:00:00.0; 9(1), p. 4410.
EPub date: 2018-10-23 00:00:00.0.
PMID: 30353012
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PHIP as a therapeutic target for driver-negative subtypes of melanoma, breast, and lung cancer.
Authors: de Semir D. , Bezrookove V. , Nosrati M. , Dar A.A. , Wu C. , Shen J. , Rieken C. , Venkatasubramanian M. , Miller J.R. , Desprez P.Y. , et al. .
Source: Proceedings Of The National Academy Of Sciences Of The United States Of America, 2018-06-19 00:00:00.0; 115(25), p. E5766-E5775.
EPub date: 2018-06-04 00:00:00.0.
PMID: 29866840
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