Abstract 4623: Notch3 in lung adenocarcinoma pathogenesis and heterogeneity

Abstract

Abstract Lung cancer is the leading cause of cancer related death worldwide. Non-small lung cancer accounts for 85% of diagnoses and the predominant subtype is lung adenocarcinoma (LUAD). LUAD has a less than 20% response rate to conventional chemotherapy and despite identification of several therapeutic targets, the majority of diagnoses continue to lead to death, highlighting the need for better treatments. Notch signaling in mammals is complex, with multiple receptors, ligands and modifiers. Notch ligands at the surface of one cell interact with receptors on an adjacent cell, triggering cleavage and nuclear translocation of the intracellular domain which interacts with Rbpj/Csl to control the transcription of target genes. In LUAD, significant evidence suggests that Notch plays an oncogenic role. Previously, we identified a population of Tumor Propagating Cells (TPC), which had greater capacity for tumor formation and are enriched after treatment with cisplatin. The TPC population was defined by the expression of CD24, ITGB4 and was Notch high. Further functional validation showed that specifically Notch3 contributes to this propagation phenotype and is key in establishing functional intra-tumoral heterogeneity. However, the TPC population is still heterogeneous and likely only a subset of these cells are true TPCs. Furthermore, the gene expression signature of the mouse TPCs has prognostic significance in human LUAD, however the TPC population hasn’t been defined in human patients, limiting our ability to target the Notch pathway therapeutically. To assess the heterogeneity of the mouse TPC population we performed FACS on tumors from KrasLSLG12D; Tp53flox/flox; YFPLSL twelve weeks after tumor initiation via AdCre. Tumors were sorted for bulk population (YFP+Lin-) and for TPC (YFP+Lin-CD24+ITGB4+Notchhi) population and single cell sequencing was performed using the 10X genomics platform. We hypothesize that aberrant Notch3 signaling is a critical pathway for survival in at least some LUAD and that Notch activation leads to gene expression changes that are important for driving human LUAD maintenance. Patient-derived xenografts (PDX) more closely recapitulate important aspects of human cancer, particularly with regards to the role of intratumoral heterogeneity and self-renewal pathways. To characterize Notch3 expressing cells in human LUAD, we performed FACS on our cohort of LUAD PDXs and sorted the Notch3+ population. We found expression of Notch3 and expression of Notch ligand Jagged2 in all LUAD tumors regardless of driver mutation. Citation Format: Kieren D. Marini, Stanley Leung, Alex Lee, Alejandro Sweet-Cordero. Notch3 in lung adenocarcinoma pathogenesis and heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4623.