Skip to main content
Grant Details

Grant Number: 5R01CA226802-05 Interpret this number
Primary Investigator: Salomonis, Nathan
Organization: Cincinnati Childrens Hosp Med Ctr
Project Title: Unbiased Identification of Spliceosome Vulnerabilities Across Cancer
Fiscal Year: 2022


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.


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; 14(649), p. eabl3981.
EPub date: 2022-06-15.
PMID: 35704600
Related Citations

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; 107(4), p. 803-815.
EPub date: 2022-04-01.
PMID: 33910331
Related Citations

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, 2021-11-05; 22(6), .
PMID: 34009266
Related Citations

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.
PMID: 33912679
Related Citations

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; , .
EPub date: 2020-12-24.
PMID: 33398286
Related Citations

Resolving single-cell heterogeneity from hundreds of thousands of cells through sequential hybrid clustering and NMF.
Authors: Venkatasubramanian M. , Chetal K. , Schnell D.J. , Atluri G. , Salomonis N. .
Source: Bioinformatics (Oxford, England), 2020-06-01; 36(12), p. 3773-3780.
PMID: 32207533
Related Citations

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; 11(1), p. 2369.
EPub date: 2020-05-12.
PMID: 32398749
Related Citations

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; 117(16), p. 9064-9073.
EPub date: 2020-04-09.
PMID: 32273388
Related Citations

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; 47(21), p. e138.
PMID: 31529053
Related Citations

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 Aug; 9(8), p. 1080-1101.
EPub date: 2019-05-13.
PMID: 31085557
Related Citations

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.
PMID: 31011167
Related Citations

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; 4(3), .
EPub date: 2019-02-07.
PMID: 30728335
Related Citations

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.
PMID: 31750239
Related Citations

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 Dec; 68, p. 51-61.
EPub date: 2018-09-21.
PMID: 30243574
Related Citations

SKI 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; 132(21), p. e24-e34.
EPub date: 2018-09-24.
PMID: 30249787
Related Citations

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; 9(1), p. 4410.
EPub date: 2018-10-23.
PMID: 30353012
Related Citations

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; 115(25), p. E5766-E5775.
EPub date: 2018-06-04.
PMID: 29866840
Related Citations

Back to Top