Longitudinal profiling of tumor evolution and drug resistance in autochthonous mouse models of Kras-driven human lung adenocarcinoma
Marjanovic D. Nemanja, Tammela Tuomas, Hofree Matan, Canner A David, Kim Jon, Smith Olivia, Jacks Tyler, Regev Aviv
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death globally. Tumors driven by expression of the KRAS oncogene account for approximately 25% of lung adenocarcinomas and, for these tumors in particular, effective chemotherapies are lacking. One possible explanation for the failure of conventional therapies and immunotherapies in cancers is the cellular heterogeneity that exists within tumors. Therefore understanding phenotypic heterogeneity at the single-cell level can be leveraged to predict mechanisms of resistance, which enables the design of effective combination therapies. Here we landscape tumor heterogeneity over the course of natural tumor evolution in autochthonous mouse models of Kras-driven human lung adenocarcinoma. Moreover we profiled transcriptional heterogeneity in Kras+/+ and p53-/- tumors as well. Tumors with this genetic background are seen in patients with more advanced tumors in clinic. We have observed explosion of cell heterogeneity within tumor during tumor progression. We have identified multiple different clusters of cells, which have been consistently present in multiple tumors and in multiple mice. This finding is particularly important because is showing us that tumors do not need only to depend on genetic mutations to evolve and give rise to different subclones. Moreover we have identified 2 different clusters of cells, which have been resistant to cisplatin treatment, which is a standard of care for these cancers. This is the first study that focuses on profiling tumor heterogeneity longitudinally. Further research will focus on the understanding resistance mechanism of these resistant subpopulations, which could yield promising targets for targeted therapy of NSCLC.
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