Abstract

Malignant neoplasms evolve in response to changes in oncogenic signalling1. Cancer cell plasticity in response to evolutionary pressures is fundamental to tumour progression and the development of therapeutic resistance2,3. Here we determine the molecular and cellular mechanisms of cancer cell plasticity in a conditional oncogenic Kras mouse model of pancreatic ductal adenocarcinoma (PDAC), a malignancy that displays considerable phenotypic diversity and morphological heterogeneity. In this model, stochastic extinction of oncogenic Kras signalling and emergence of Kras-independent escaper populations (cells that acquire oncogenic properties) are associated with de-differentiation and aggressive biological behaviour. Transcriptomic and functional analyses of Kras-independent escapers reveal the presence of Smarcb1Myc-network-driven mesenchymal reprogramming and independence from MAPK signalling. A somatic mosaic model of PDAC, which allows time-restricted perturbation of cell fate, shows that depletion of Smarcb1 activates the Myc network, driving an anabolic switch that increases protein metabolism and adaptive activation of endoplasmic-reticulum-stress-induced survival pathways. Increased protein turnover renders mesenchymal sub-populations highly susceptible to pharmacological and genetic perturbation of the cellular proteostatic machinery and the IRE1-α–MKK4 arm of the endoplasmic-reticulum-stress-response pathway. Specifically, combination regimens that impair the unfolded protein responses block the emergence of aggressive mesenchymal subpopulations in mouse and patient-derived PDAC models. These molecular and biological insights inform a potential therapeutic strategy for targeting aggressive mesenchymal features of PDAC.

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Acknowledgements

We thank D. Spring, A. Futreal, P. Jones, J. Marszalek, I. Watson, Y. Lissanu Deribe, K. Rai and J. Horner for discussions and suggestions. We thank A. Petrocchi, E. Di Francesco, E. Paul and T. Tieu for providing reagents. We wish to thank the members of the Chin, DePinho and Draetta labs for discussions and reagents; K. Dunner, Jr. and the High Resolution Electron Microscopy Facility at MDACC for TEM (Cancer Center Core Grant CA16672); M. Keith, C. Kingsley, the MDACC Small Animals Imaging Facility, the UTMDACC Microarray Core Facility, the MDACC Department of Veterinary Medicine and the UTMDACC Flow Facility. L.C. was supported by the CPRIT R1204 and NIH 5 U01 CA141508. G.F.D. was supported by the AACR 14-90-25 and by the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Grant. A.C. was supported by the FIRC (Fondazione Italiana per la Ricerca sul Cancro) Fellowship. G.G. was supported by the FIRC fellowship.

Author information

Author notes

    • Alessandro Carugo
    • , Timothy P. Heffernan
    •  & Lynda Chin

    Present addresses: C4 Therapeutics, Cambridge, Massachusetts 02142, USA (T.P.H.); Institute for Health Transformation, The University of Texas System, Austin, Texas 78701, USA (L.C.)

    • James Tepper
    • , Frederick Scott Robinson
    •  & Liren Li

    These authors contributed equally to this work.

Affiliations

  1. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Giannicola Genovese
    • , Alessandro Carugo
    • , James Tepper
    • , Frederick Scott Robinson
    • , Liren Li
    • , Maria Svelto
    • , Luigi Nezi
    • , Denise Corti
    • , Rosalba Minelli
    • , Piergiorgio Pettazzoni
    • , Tony Gutschner
    • , Chia-Chin Wu
    • , Sahil Seth
    • , Kadir Caner Akdemir
    • , Samirkumar Amin
    • , Koichi Takahashi
    • , Andrea Viale
    • , Giulio F. Draetta
    •  & Lynda Chin
  2. Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Alessandro Carugo
    • , Frederick Scott Robinson
    • , Elisabetta Leo
    • , Virginia Giuliani
    • , Jill Garvey
    • , Jianhua Zhang
    • , Timothy P. Heffernan
    • , Giulio F. Draetta
    •  & Lynda Chin
  3. European Institute of Oncology, Milano 20141, Italy

    • Alessandro Carugo
  4. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, 510060, China

    • Liren Li
  5. Istituto di Patologia Generale, Universitá Cattolica del Sacro Cuore, Rome 00168, Italy

    • Maria Svelto
    •  & Alessandro Sgambato
  6. Graduate program in Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA

    • Samirkumar Amin
  7. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, Maryland 21287, USA

    • Marco Dal Molin
    • , Michael G. Goggins
    •  & Laura D. Wood
  8. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Haoqiang Ying
  9. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Lawrence N. Kwong
  10. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Simona Colla
    •  & Koichi Takahashi
  11. Office of Technology Commercialization, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Papia Ghosh
  12. Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Florian Muller
  13. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Prasenjit Dey
    • , Shan Jiang
    •  & Ronald A. DePinho
  14. Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Chang-Gong Liu
  15. ORBIT Platform, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Carlo Toniatti
  16. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Jason B. Fleming
  17. Department of Pathology, Friedrich Alexander University Erlangen-Nuremberg, University Hospital, Erlangen 91054, Germany

    • Abbas Agaimy
  18. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Anirban Maitra
    •  & Huamin Wang
  19. Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Anirban Maitra
  20. Comprehensive Cancer Center and Department of Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee 77027, USA

    • Charles W. M. Roberts

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Contributions

G.G. designed the study with input from L.C., G.F.D., P.G., A.C., C.W.M.R., A.V., T.G., R.A.D. and other authors. In vitro experiments were performed by G.G., M.S., F.S.R., J.T., D.C. and A.C. Viral vectors were designed by G.G. and M.S. with input from S.C. and A.C. In vivo studies were performed by G.G., L.L., A.C., J.T. and P.P. with help from T.G., K.T. and F.M. The mouse colonies were maintained and genotyped by F.S.R., G.G. and A.C. with help from S.J. and J.G. Immunohistochemistry and immunofluorescence were performed by G.G., J.T., L.N. and A.V. FACS studies were performed by A.V. and E.L. FACS data analysis was performed by A.V. and E.L. Drug studies were performed by G.G. and J.T. with the help of P.P., T.P.H., C.T. and V.G. Bioinformatic analysis was performed by S.S., K.C.A., S.A. and J.Z. with input from G.G., L.N.K. and A.C. Human tissues were obtained by H.W., J.B.F., A.S., A.M., M.D.M., M.G.G., L.D.W. and A.A. Slides were scored by H.W. and G.G. G.G., A.C., G.F.D., P.G. and L.C. reviewed statistical analysis and proof-read the final version of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Giannicola Genovese or Giulio F. Draetta.

Reviewer Information Nature thanks Z. Ronai and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature21064

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