Primary Tumor Genotype Is an Important Determinant in Identification of Lung Cancer Propagating Cells

Abstract

Successful cancer therapy requires the elimination or incapacitation of all tumor cells capable of regenerating a tumor. Therapeutic advances therefore necessitate the characterization of the cells that are able to propagate a tumor in vivo. We show an important link between tumor genotype and isolation of tumor-propagating cells (TPCs). Three mouse models of the most common form of human lung cancer each had TPCs with a unique cell surface phenotype. The cell surface marker Sca1 did not enrich for TPCs in tumors initiated with oncogenic Kras, and only Sca1-negative cells propagated EGFR mutant tumors. In contrast, Sca1-positive cells were enriched for tumor-propagating activity in Kras tumors with p53 deficiency. Primary tumors that differ in genotype at just one locus can therefore have tumor-propagating cell populations with distinct markers. Our studies show that the genotype of tumor samples must be considered in studies to identify, characterize, and target tumor-propagating cells.

Summary Depending on the tumor initiating genetic event in three tractable mouse models of lung adenocarcinoma, the surface maker Sca1 had variable success in identifying cells with tumor-propagating activity. These findings uncover the impact that tumor genotype can have on the phenotype of tumor-propagating cells, which may have important therapeutic significance.

Highlights -identification of the first lung tumor-propagating cell population -lung cancers of different genotype have tumor-propagating cells with distinct markers -tumor samples should be separated by genotype to study tumor-propagating cells