Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis | Science
Cassandra Burdziak https://orcid.org/0000-0001-6008-7783, Direna Alonso-Curbelo https://orcid.org/0000-0001-6674-3059, Thomas Walle https://orcid.org/0000-0003-4835-955X, José Reyes https://orcid.org/0000-0002-1133-4933, Francisco M. Barriga, Doron Haviv, Yubin Xie https://orcid.org/0000-0003-2542-2544, Zhen Zhao https://orcid.org/0000-0001-5271-4759, Chujun Julia Zhao https://orcid.org/0000-0002-9792-4722, Hsuan-An Chen https://orcid.org/0000-0002-8979-3670, Ojasvi Chaudhary, Ignas Masilionis https://orcid.org/0000-0001-7937-9014, Zi-Ning Choo, Vianne Gao, Wei Luan, Alexandra Wuest, Yu-Jui Ho https://orcid.org/0000-0002-7540-024X, Yuhong Wei https://orcid.org/0000-0003-2064-4826, Daniela F. Quail https://orcid.org/0000-0002-6969-3250, Richard Koche https://orcid.org/0000-0002-6820-5083, Linas Mazutis https://orcid.org/0000-0002-5552-6427, Ronan Chaligné https://orcid.org/0000-0003-4332-3291, Tal Nawy https://orcid.org/0000-0003-3720-3699, Scott W. Lowe https://orcid.org/0000-0002-5284-9650 [email protected], and Dana Pe’er https://orcid.org/0000-0002-9259-8817 [email protected]Authors Info & Affiliations
Science
12 May 2023
Vol 380, Issue 6645
Editor’s summary
The development of pancreatic cancer involves a complex interplay between pancreatic lesions and the surrounding tissue microenvironment. Burdziak et al. performed an in-depth analysis of the evolution of pancreatic tumors. Using several model systems, including newly developed computational methods, tumor progression stages leading to pancreatic adenocarcinoma were predicted based upon communication gene modules. Tissue remodeling was traced from a healthy pancreas to an inflamed state, the premalignant stage, and then to full-blown malignancy and distant metastasis. Epigenetic plasticity in early progenitor–like epithelial cells primed pancreatic cells for neoplastic transformation. Plasticity was associated with the remodeling of accessible chromatin close to cell-cell signaling genes and an interleukin-33–mediated inflammatory feedback loop between epithelial and immune cells. —Priscilla N. Kelly
Structured Abstract
INTRODUCTION
Virtually all cancers begin with genetic alterations in healthy cells, but mounting evidence suggests that nongenetic events such as environmental signaling play a crucial role in unleashing tumorigenesis. In the pancreas, epithelial cells harboring an activating mutation in the Kras proto-oncogene can remain phenotypically normal until an inflammatory event that drives cellular plasticity and tissue remodeling. The inflammation-driven molecular, cellular, and tissue changes that precede and direct tumor formation remain poorly understood.
RATIONALE
Understanding tumorigenesis requires a high-resolution view of events spanning cancer progression. We leveraged genetically engineered mouse models (GEMMs), single-cell genomics (RNA sequencing and assay for transposase-accessible chromatin sequencing), and imaging technologies to measure pancreatic epithelial cell states across physiological, premalignant, and malignant stages. To analyze this rich and complex dataset, we developed computational and functional approaches to characterize epigenetic plasticity and to infer cell-cell communication impacts on tissue remodeling.
RESULTS
Our data revealed that early in tumorigenesis, Kras-mutant cells are capable of acquiring multiple highly reproducible cell states that are undetectable in normal or regenerating pancreata. Several such states align with experimentally validated cells of origin of neoplastic lesions, some of which display a high degree of plasticity upon inflammatory insult. These diverse Kras-mutant cell populations are defined by distinct chromatin accessibility patterns and undergo inflammation-driven cell fate transitions that precede preneoplastic and premalignant lesion formation. Furthermore, a subset of early Kras-mutant cell states exhibit marked similarity to either benign or malignant fates that emerge weeks to months later; for instance, Kras-mutant Nestin-positive progenitor-like cells display accessible chromatin near genes active in malignant tumors.
We defined and quantified epigenetic plasticity as the diversity in transcriptional phenotypes that is enabled or restricted by a given epigenetic accessibility landscape. These plastic cell states are enriched for open chromatin near cell-cell communication genes encoding ligands and cell-surface receptors, suggesting an increased propensity to communicate with the microenvironment. Given the rapid remodeling of both the epithelial and immune compartments during inflammation, we hypothesize that this epigenetically enabled communication is a major driver of tumorigenesis. We found that the premalignant epithelium displays extraordinary modularity with respect to communication gene coexpression patterns, with distinct cell subpopulations each expressing a unique set of receptors and ligands that define the nature of incoming and outgoing signals that they can receive and send.
Through the development of Calligraphy, an algorithm that utilizes this receptor-ligand modularity to robustly infer the cell-cell communication underlying tissue remodeling, we showed that the enhanced signaling repertoire of early neoplastic tissue endows specific plastic epithelial populations with greater capability for cross-talk, including numerous communication routes with immune populations. As one example, we identified a feedback loop between inflammation-driven Kras-mutant epithelial and immune cell states involving interleukin-33 (IL-33), which was previously implicated in pancreatic tumorigenesis. Using a new GEMM that enables spatiotemporally controlled suppression of epithelial Il33 expression during mutant Kras-initiated neoplasia, we functionally demonstrated that the loop initiated by epithelial IL-33 directs exit from a highly plastic, inflammation-induced epithelial state, enabling progression toward typical neoplasia.
CONCLUSION
Multimodal single-cell profiling of tumorigenesis in mouse models identified the cellular and tissue determinants of pancreatic cancer initiation, and a rigorous quantification of plasticity enabled the discovery of plasticity-associated gene programs. We found that Kras-mutant subpopulations markedly increase epigenetic plasticity upon inflammation, reshaping their communication potential with immune cells and establishing aberrant cell-cell communication loops that drive their progression toward neoplastic lesions.
Abstract
The response to tumor-initiating inflammatory and genetic insults can vary among morphologically indistinguishable cells, suggesting as yet uncharacterized roles for epigenetic plasticity during early neoplasia. To investigate the origins and impact of such plasticity, we performed single-cell analyses on normal, inflamed, premalignant, and malignant tissues in autochthonous models of pancreatic cancer. We reproducibly identified heterogeneous cell states that are primed for diverse, late-emerging neoplastic fates and linked these to chromatin remodeling at cell-cell communication loci. Using an inference approach, we revealed signaling gene modules and tissue-level cross-talk, including a neoplasia-driving feedback loop between discrete epithelial and immune cell populations that was functionally validated in mice. Our results uncover a neoplasia-specific tissue-remodeling program that may be exploited for pancreatic cancer interception.
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Supplementary Materials
This PDF file includes:
Materials and Methods
Figs. S1 to S13
Tables S2, S8, S9, S11 to S13, S15 to S17
References (71–101)
Other Supplementary Material for this manuscript includes the following:
Tables S1, S3 to S7, S10, S14, and S18
MDAR Reproducibility Checklist
References and Notes
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Volume 380 | Issue 6645
12 May 2023
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Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Acknowledgments
We thank J. Simon and the MSKCC animal facility for technical support with animal colonies; MSKCC Flow Cytometry facility for support with FACS sorting experiments; the Single Cell and Imaging Mass Cytometry Platform at Goodman Cancer Research Centre; the members of the Sloan Kettering Institute’s Single Cell Analytics and Innovation Lab (SAIL) computational unit, and members of the Lowe and Pe’er laboratories for advice and discussions, in particular M. Setty and A. Chaikovsky for foundational scRNA-seq analyses and critically revising the final manuscript, respectively. We also thank J. Moffitt, B. Watson, J. Hurley, and S. Aviles for generously sharing their knowledge, protocols, and guidance to help us set up the multiplex smFISH platform in the lab and S. Gan and D. V. Kumar Yarlagadda for pivotal contributions to establishing our infrastructure for multiplex smFISH imaging.
Funding: This work was supported by Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center (GMTEC) funding and National Cancer Institute (NCI) Cancer Center Support grant P30 CA008748. C.B. is supported by a Ruth L. Kirschtein Predoctoral Fellowship (National Cancer Institute grant F31CA24690). D.A.C. is supported by La Caixa Junior Leader Fellowship LCF/BQ/PI20/11760006 and FERO-ASEICA grant BFERO2021 from the FERO Foundation and Spanish Cancer Research Association and Spanish Ministry of Science and Innovation grant PID2021-128102OA-I00. F.M.B. is supported by an Edward P. Evans Young Investigator Award. T.W. is supported by a fellowship from the DKFZ Clinician Scientist Program, supported by the Dieter Morszeck Foundation. SCIMAP is supported by the Fraser Memorial Trust and a McGill MI4 Platform grant. J.R. is a Howard Hughes Medical Institute Fellow of the Damon Runyon Cancer Research Foundation (grant DRG-2382-19). C.J.Z. is supported by National Institutes of Health grant R25 CA233208. S.W.L. is an investigator in the Howard Hughes Medical Institute and the Geoffrey Beene Chair for Cancer Biology. D.P. is an investigator in the Howard Hughes Medical Institute, is an Alan and Sandra Gerry Endowed Chair, and is supported by NCI grant U54 CA209975, National Institute of Child Health and Human Development DP1 grant HD084071, and the Starr Cancer Consortium.
Author contributions: Conceptualization: C.B., D.A.-C., S.W.L., D.P.; Data curation: C.B., D.A.-C., T.W., J.R., D.H., Y.X., V.G., Y.-J.H.; Formal analysis: C.B., T.W., D.H., Y.X., C.J.Z., R.K.; Funding acquisition: C.B., D.A.-C., S.W.L., D.P.; Investigation: C.B., D.A.-C., T.W., J.R., F.M.B., D.H., Y.X., Z.Z., H.-A.C., O.C., I.M., W.L., A.W., L.M., R.C.; Methodology: C.B., D.A.-C., S.W.L., D.P.; Resources: Z.-N.C., Y.W., D.Q.; Software: C.B.; Supervision: S.W.L., D.P.; Visualization: C.B., D.A.-C., T.W.; Writing – original draft: C.B., D.A.-C., T.N., S.W.L., D.P.; Writing – review & editing: T.W., J.R.
Competing interests: S.W.L. is a consultant and holds equity in Blueprint Medicines, ORIC Pharmaceuticals, Mirimus Inc., PMV Pharmaceuticals, Faeth Therapeutics, and Constellation Pharmaceuticals. D.A.-C. and S.W.L. are listed as the inventors for patent application (PTC/US2019/041670, internationally filing date 12 July 2019) covering methods for preventing or treating KRAS mutant pancreas cancer with inhibitors of type 2 cytokine signaling. D.P. is on the scientific advisory board of Insitro. T.W. reports stock ownership for Roche, Bayer, Innate Pharma, Illumina, and 10x Genomics, as well as research funding (not related to this study) from CanVirex AG, Basel Switzerland, and Institut für Klinische Krebsforschung GmbH, Frankfurt, Germany. C.B., D.A.-C., S.W.L., and D.P. are listed as inventors on a provisional patent application (63/390,075) related to methods and compositions for treating PDAC, for which Memorial Sloan Kettering Cancer Center is the applicant.
Data and materials availability: All sequencing data have been deposited at the Gene Expression Omnibus (GEO) under accession number GSE207943. An interactive data browser to plot gene expression trends on tSNE or FDL visualizations of scRNA-seq data is accessible at http://pdac-progression-browser.us-east-1.elasticbeanstalk.com. Code for data analysis is available at github (https://github.com/dpeerlab/pdac-progression) and Zenodo (70). KC-shIL33 ESCs for the production of EPO-GEMMs are available from S.W.L. upon request.
Authors
Affiliations
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Roles: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, and Writing – review & editing.
Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.
Roles: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Supervision, Visualization, Writing – original draft, and Writing – review & editing.
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Clinical Cooperation Unit Virotherapy, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, 69120 Heidelberg, Germany.
German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
Roles: Conceptualization, Data curation, Formal analysis, Software, Validation, Visualization, and Writing – review & editing.
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Roles: Conceptualization, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing – original draft, and Writing – review & editing.
Francisco M. Barriga
Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Role: Investigation.
Doron Haviv
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Roles: Formal analysis, Software, and Validation.
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Roles: Formal analysis, Investigation, Resources, Software, Validation, Visualization, and Writing – review & editing.
Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Roles: Investigation, Methodology, and Resources.
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
Roles: Formal analysis, Software, and Validation.
Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Roles: Investigation, Methodology, and Resources.
Ojasvi Chaudhary
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Role: Investigation.
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Role: Investigation.
Zi-Ning Choo
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Role: Software.
Vianne Gao
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Tri-Institutional Training Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY 10065, USA.
Roles: Data curation, Formal analysis, Investigation, and Software.
Wei Luan
Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Alexandra Wuest
Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Role: Investigation.
Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Roles: Formal analysis and Software.
Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Quebec H3A 1A3, Canada.
Roles: Investigation, Methodology, and Resources.
Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, Quebec H3A 1A3, Canada.
Role: Methodology.
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Roles: Data curation, Formal analysis, Resources, Software, and Visualization.
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA.
Institute of Biotechnology, Life Sciences Centre, Vilnius University, 02158 Vilnius, Lithuania.
Roles: Formal analysis, Investigation, and Methodology.
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Roles: Project administration and Supervision.
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Roles: Writing – original draft and Writing – review & editing.
Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Roles: Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, and Validation.
Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
Roles: Conceptualization, Formal analysis, Funding acquisition, Methodology, Project administration, Software, Supervision, Validation, Visualization, and Writing – original draft.
Funding Information
Fraser Memorial Trust
McGill MI4 Platform Grant
NIH Research Education Program: R25 CA233208
Edward P. Evans Young Investigator Award
DKFZ Clinician Scientist Program (Dieter Morszeck Foundation)
Alan and Sandra Gerry Endowed Chair
FERO-ASEICA: BFERO2021
Spanish Ministry of Science and Innovation grant: PID2021-128102OA-I00
La Caixa Junior Leader Fellowship: LCF/BQ/PI20/11760006
Notes
†
These authors contributed equally to this work.
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- Cassandra Burdziak
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Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis.Science380,eadd5327(2023).DOI:10.1126/science.add5327
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