Abstract 266: Notch3 is a marker of tumor-propagating cells in non-small cell lung cancer and is required for their self-renewal.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC We investigated tumor cell heterogeneity in mouse models of non-small cell lung cancer (NSCLC) that recapitulate key genetic events in this disease. In tumors driven by simultaneous expression of an oncogenic Kras allele and loss of the tumor suppressor Trp53, only a relatively rare subset of tumor cells is capable of propagating tumor growth in both a clonogenic in vitro assay and an in vivo orthotopic transplantation assay. The tumor-propagating cell (TPC) population was enriched by sorting for the combination of the cell surface markers CD24, ITGB4 and Notch(1-4). We demonstrate a critical and specific role for Notch3 signaling in the maintenance of TPCs in the KrasG12D; Trp53fl/fl mouse model. Knock-down of Notch3, but not Notch 1, 2 or 4, decreased self-renewal of TPCs in vitro. In addition, knock-down of Notch3 was critical for tumor propagation in vivo. The relevance of these studies to human NSCLC was confirmed by demonstrating a significant effect of Notch inhibition on the self-renewal of primary human lung adenocarcinoma cells in ex vivo cultures established directly from patients. These findings identify a novel subpopulation of tumor cells with distinct functional capabilities, underscoring the importance of interrogating heterogeneity in NSCLC. The unique role of Notch3 in tumor propagation may provide a novel therapeutic target for the treatment of non-small cell lung cancer.   Citation Format: Yanyan Zheng, Cecile de la Cruz, Leanne Sayles, Chris Alleyne-Chin, Yue Xu, Chuong D. Hoang, Joseph B. Shrager, Erica Jackson, Alejandro Sweet-Cordero. Notch3 is a marker of tumor-propagating cells in non-small cell lung cancer and is required for their self-renewal. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 266. doi:10.1158/1538-7445.AM2013-266