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Lineage-restricted neoplasia driven by Myc defaults to small cell lung cancer when combined with loss of p53 and Rb in the airway epithelium

Oncogene volume 41, pages 138–145 (2022)Cite this article

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Abstract

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by loss of function TP53 and RB1 mutations in addition to mutations in other oncogenes including MYC. Overexpression of MYC together with Trp53 and Rb1 loss in pulmonary neuroendocrine cells of the mouse lung drives an aggressive neuroendocrine low variant subtype of SCLC. However, the transforming potential of MYC amplification alone on airway epithelium is unclear. Therefore, we selectively and conditionally overexpressed MYC stochastically throughout the airway or specifically in neuroendocrine, club, or alveolar type II cells in the adult mouse lung. We observed that MYC overexpression induced carcinoma in situ which did not progress to invasive disease. The formation of adenoma or SCLC carcinoma in situ was dependent on the cell of origin. In contrast, MYC overexpression combined with conditional deletion of both Trp53 and Rb1 exclusively gave rise to SCLC, irrespective of the cell lineage of origin. However, cell of origin influenced disease latency, metastatic potential, and the transcriptional profile of the SCLC phenotype. Together this reveals that MYC overexpression alone provides a proliferative advantage but when combined with deletion of Trp53 and Rb1 it facilitates the formation of aggressive SCLC from multiple cell lineages.

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Fig. 1: Cell lineage restricted MYC overexpression dictates lung tumor type.
Fig. 2: MYC over-expression in Rb1 and Trp53 defaults to SCLC development.
Fig. 3: Trp53, Rb1 deletion, and MYC overexpression drive SCLC irrespective of the cell of origin.
Fig. 4: Unique transcriptional signatures dependent on cell of origin.

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References

  1. Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol: Off J Am Soc Clin Oncol. 2006;24:4539–44.

    Article  Google Scholar 

  2. Farago AF, Keane FK. Current standards for clinical management of small cell lung cancer. Transl Lung Cancer Res. 2018;7:69–79.

    Article  Google Scholar 

  3. George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524:47–53. Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t

    Article  CAS  Google Scholar 

  4. Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44:1104–10. Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t

    Article  CAS  Google Scholar 

  5. Voortman J, Lee JH, Killian JK, Suuriniemi M, Wang Y, Lucchi M, et al. Array comparative genomic hybridization-based characterization of genetic alterations in pulmonary neuroendocrine tumors. Proc Natl Acad Sci USA. 2010;107:13040–5.

    Article  CAS  Google Scholar 

  6. Johnson BE, Russell E, Simmons AM, Phelps R, Steinberg SM, Ihde DC, et al. MYC family DNA amplification in 126 tumor cell lines from patients with small cell lung cancer. J Cell Biochem Suppl. 1996;24:210–7.

    Article  CAS  Google Scholar 

  7. Alves Rde C, Meurer RT, Roehe AV. MYC amplification is associated with poor survival in small cell lung cancer: a chromogenic in situ hybridization study. J cancer Res Clin Oncol. 2014;140:2021–5.

    Article  Google Scholar 

  8. Mollaoglu G, Guthrie MR, Bohm S, Bragelmann J, Can I, Ballieu PM, et al. MYC drives progression of small cell lung cancer to a variant neuroendocrine subtype with vulnerability to aurora kinase inhibition. Cancer cell. 2017;31:270–285.

    Article  CAS  Google Scholar 

  9. Rudin CM, Poirier JT, Byers LA, Dive C, Dowlati A, George J, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 2019;19:289–97.

    Article  CAS  Google Scholar 

  10. Ireland AS, Micinski AM, Kastner DW, Guo B, Wait SJ, Spainhower KB, et al. MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate. Cancer cell. 2020;38:60–78.e12.

    Article  CAS  Google Scholar 

  11. Sutherland KD, Proost N, Brouns I, Adriaensen D, Song JY, Berns A. Cell of origin of small cell lung cancer: inactivation of Trp53 and Rb1 in distinct cell types of adult mouse lung. Cancer cell. 2011;19:754–64. Research Support, Non-U.S. Gov’t

    Article  CAS  Google Scholar 

  12. Calado DP, Sasaki Y, Godinho SA, Pellerin A, Kochert K, Sleckman BP, et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nat Immunol. 2012;13:1092–1100.

    Article  CAS  Google Scholar 

  13. Yang D, Denny SK, Greenside PG, Chaikovsky AC, Brady JJ, Ouadah Y, et al. Intertumoral heterogeneity in SCLC is influenced by the cell type of origin. Cancer discov. 2018.

  14. Plasschaert LW, Zilionis R, Choo-Wing R, Savova V, Knehr J, Roma G, et al. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature. 2018;560:377–81.

    Article  CAS  Google Scholar 

  15. Simpson DS, Mason-Richie NA, Gettler CA, Wikenheiser-Brokamp KA. Retinoblastoma family proteins have distinct functions in pulmonary epithelial cells in vivo critical for suppressing cell growth and tumorigenesis. Cancer Res. 2009;69:8733.

    Article  CAS  Google Scholar 

  16. Wikenheiser-Brokamp KA. Rb family proteins differentially regulate distinct cell lineages during epithelial development. Dev (Camb, Engl). 2004;131:4299.

    Article  CAS  Google Scholar 

  17. Crapo JD, Barry BE, Gehr P, Bachofen M, Weibel ER. Cell number and cell characteristics of the normal human lung. Am Rev Respir Dis. 1982;126:332–7.

    CAS  PubMed  Google Scholar 

  18. Boers JE, Ambergen AW, Thunnissen FB. Number and proliferation of clara cells in normal human airway epithelium. Am J Respir Crit Care Med. 1999;159:1585–91.

    Article  CAS  Google Scholar 

  19. Grunblatt E, Wu N, Zhang H, Liu X, Norton JP, Ohol Y, et al. MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity. Genes Dev. 2020;34:1210–26.

    Article  CAS  Google Scholar 

  20. Denny SK, Yang D, Chuang CH, Brady JJ, Lim JS, Gruner BM, et al. Nfib promotes metastasis through a widespread increase in chromatin accessibility. Cell. 2016;166:328–42.

    Article  CAS  Google Scholar 

  21. Semenova EA, Kwon MC, Monkhorst K, Song JY, Bhaskaran R, Krijgsman O, et al. Transcription factor NFIB is a driver of small cell lung cancer progression in mice and marks metastatic disease in patients. Cell Rep. 2016;16:631–43.

    Article  CAS  Google Scholar 

  22. Zhang W, Girard L, Zhang YA, Haruki T, Papari-Zareei M, Stastny V, et al. Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. Transl Lung Cancer Res. 2018;7:32–49.

    Article  Google Scholar 

  23. Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417–25.

    Article  CAS  Google Scholar 

  24. Morton JP, Sansom OJ. MYC-y mice: from tumour initiation to therapeutic targeting of endogenous MYC. Mol Oncol. 2013;7:248–58.

    Article  CAS  Google Scholar 

  25. Geick A, Redecker P, Ehrhardt A, Klocke R, Paul D, Halter R. Uteroglobin promoter-targeted c-MYC expression in transgenic mice cause hyperplasia of Clara cells and malignant transformation of T-lymphoblasts and tubular epithelial cells. Transgenic Res. 2001;10:501–11.

    Article  CAS  Google Scholar 

  26. Ehrhardt A, Bartels T, Geick A, Klocke R, Paul D, Halter R. Development of pulmonary bronchiolo-alveolar adenocarcinomas in transgenic mice overexpressing murine c-myc and epidermal growth factor in alveolar type II pneumocytes. Br J cancer. 2001;84:813–8.

    Article  CAS  Google Scholar 

  27. Huang YH, Klingbeil O, He XY, Wu XS, Arun G, Lu B, et al. POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer. Genes Dev. 2018;32:915–28.

    Article  CAS  Google Scholar 

  28. Olsen RR, Ireland AS, Kastner DW, Groves SM, Spainhower KB, Pozo K, et al. ASCL1 represses a SOX9(+) neural crest stem-like state in small cell lung cancer. Genes Dev. 2021;35:847–69.

    Article  CAS  Google Scholar 

  29. Burr ML, Sparbier CE, Chan KL, Chan YC, Kersbergen A, Lam EYN, et al. An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer. Cancer cell. 2019;36:385–401. e388

    Article  CAS  Google Scholar 

  30. Kortlever RM, Sodir NM, Wilson CH, Burkhart DL, Pellegrinet L, Brown Swigart L, et al. Myc cooperates with ras by programming inflammation and immune suppression. Cell. 2017;171:1301–15. e1314

    Article  CAS  Google Scholar 

  31. Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220–9.

    Article  CAS  Google Scholar 

  32. Foroutan M, Bhuva DD, Lyu R, Horan K, Cursons J, Davis MJ. Single sample scoring of molecular phenotypes. BMC Bioinforma. 2018;19:404.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank Dr. Kate Sutherland for Ad5-Cre viruses and helpful discussions. We thank the Monash Health Translational Precinct Histology Platform, Monash MicroImaging, Monash Medical Center Animal Facility, Monash Health Translational Precinct Flow Cytometry Core, Monash Biomedical Imaging, Beijing Genomics Institute (BGI) and the Monash Bioinformatics Platform for providing core and technical services.

Funding

This work was supported by the Operational Infrastructure Support Program by the Victorian Government of Australia. D.J. Gough is supported by a Victorian Cancer Agency Mid-Career Fellowship (MCRF19033) and a grant in aid from the Cancer Council of Victoria (GNT1140528).

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Authors and Affiliations

  1. Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, VIC, 3168, Australia

    Jasmine Chen, Aleks Guanizo, Quinton Luong, W. Samantha N. Jayasekara, Dhilshan Jayasinghe, Chaitanya Inampudi, Anette Szczepny, Daniel J. Garama, Vinod Ganju, Jason E. Cain & Daniel J. Gough

  2. Department of Molecular and Translational Science, Monash University, 27-31 Wright Street, Clayton, VIC, 3168, Australia

    Jasmine Chen, Aleks Guanizo, Quinton Luong, W. Samantha N. Jayasekara, Dhilshan Jayasinghe, Chaitanya Inampudi, Anette Szczepny, Daniel J. Garama, Vinod Ganju, Jason E. Cain & Daniel J. Gough

  3. Department of Anatomical Pathology, St Vincent’s Hospital, Fitzroy, Melbourne, VIC, Australia

    Prudence A. Russell

  4. Research Institute in Oncology and Hematology, Cancer Care Manitoba, Winnipeg, MB, R3E 0V9, Canada

    D. Neil Watkins

  5. Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, R3T 2N2, Canada

    D. Neil Watkins

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Study conception and design DJG. Experiments and Data Analysis: all authors, Manuscript writing DJG and JC, manuscript editing all authors.

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Correspondence to Daniel J. Gough.

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Chen, J., Guanizo, A., Luong, Q. et al. Lineage-restricted neoplasia driven by Myc defaults to small cell lung cancer when combined with loss of p53 and Rb in the airway epithelium. Oncogene 41, 138–145 (2022). https://doi.org/10.1038/s41388-021-02070-3

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