| Description |
The clinical management of small cell lung cancer (SCLC) has primarily relied on chemotherapy for the last 40 years where all tumors are treated the same way regardless of their mutational status. MYC family member genes are frequently amplified in small cell lung tumors and cell lines in a mutually exclusive way. We developed a novel genetically engineered mouse model, in which we combined Myc ectopic expression with deletions of Trp53 and Rb1, two tumor-suppressor genes orthologs of which (i.e., TP53 and RB1) are almost universally lost together in human SCLC. For the first time, we demonstrated that MYC drives a neuroendocrine-low variant subtype of SCLC. In addition to the aggressive nature of these tumors such as rapid tumor growth and metastasis, we found that MYC-driven SCLC is specifically sensitive to Aurora kinase inhibition. Therefore, our findings not only revealed that MYC family oncogenes are responsible for tumor heterogeneity but also that SCLC should be stratified based on their genetics for subtype-specific targeted therapies. The majority of non-small cell lung cancers (NSCLC) are classified as lung adenocarcinoma (LADC) or lung squamous cell carcinoma (LSCC). SOX2 and NKX2-1 are the most frequently amplified genes in LSCC and LADC, respectively. SOX2 is a wellknown oncogene for LSCC while NKX2-1 has context-dependent oncogenic and tumorsuppressive functions in LADC. We report that SOX2-driven squamous mouse tumors recapitulate cellular and molecular features of human lung squamous tumors faithfully, iv including the tumor immune microenvironment (TIME). We found that NKX2-1 is a tumorsuppressor gene for LSCC, and deletion of Nkx2-1 significantly accelerates squamous tumorigenesis. Importantly, we discovered the genetic mechanism behind differential neutrophil recruitment in lung cancer. Specifically, SOX2 and NKX2-1 inversely regulate neutrophil chemotaxis to lung cancer, partly through transcriptional regulation of the chemokine Cxcl5. We identified that a subset of tumor-associated neutrophils in LSCC is protumorigenic and surprisingly provides preferential support to squamous tumors over adenocarcinomas. These findings provide a novel example of the emerging paradigm of how cancer cell intrinsic genetic programs can shape the TIME in addition to the unexpected biology of how the modified TIME, in turn, can influence cancer cell fate. |
