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

Autor: Aleks C. Guanizo, Daniel J. Gough, Anette Szczepny, D. Neil Watkins, Quinton Luong, Vinod Ganju, Prudence A. Russell, Jasmine Chen, Daniel J. Garama, Dhilshan Jayasinghe, Chaitanya Inampudi, W. Samantha N. Jayasekara, Jason E. Cain
Rok vydání: 2021
Předmět:
Zdroj: Oncogene. 41:138-145
ISSN: 1476-5594
0950-9232
DOI: 10.1038/s41388-021-02070-3
Popis: 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.
Databáze: OpenAIRE
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