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Notch3 in Human Lung Adenocarcinoma Pathogenesis and Heterogeneity

Institution: University of California, San Francisco
Investigator(s): Kieren Marini,
Award Cycle: 2019 (Cycle 29) Grant #: T29FT0417 Award: $176,982
Subject Area: Cancer
Award Type: Postdoctoral Fellowship Awards

Initial Award 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). KRAS mutant LUAD is strongly tobacco associated and has a poor prognosis due to resistance to current targeted therapies, that are effective in other adenocarcinoma subtypes, and poor response to conventional chemotherapy. Notch signaling in mammals is complex, with four receptors, five canonical ligands and multiple signaling activators. Normally, Notch ligands at the surface of one cell interact with receptors on an adjacent cell, triggering cleavage of the internal part of the Notch receptor leading to transport into the nuclease resulting in transcription of target genes. The Sweet-Cordero lab showed that while all 4 Notch receptors are expressed on the surface of cancer stem cells, only Notch3 signaling is essential for their ability to self-renew and significant evidence suggests that Notch plays a role in tumor formation. Further to this expression of transcriptional targets of Notch3 suggested poorer prognosis in LUAD patients. Whilst we have identified that Notch is important, a precise understanding of the mechanisms of Notch signaling in this disease is lacking, limiting our ability to target the Notch pathway therapeutically in LUAD. We hypothesize that aberrant Notch3 signaling is a critical pathway for survival and that Notch activation leads to gene expression changes that are important for driving human LUAD tumor initiation and maintenance. Patient-derived xenografts (PDX) models recapitulate important aspects of human cancer biology, particularly with regards to the role of intratumoral heterogeneity and self-renewal pathways. Thus, we will use PDX models developed in our laboratory to characterize the mechanisms of Notch3 activation and the downstream consequences of this activation in human LUAD. By identifying key components of the Notch signaling pathway in both the cancer stem cells and the tumor bulk we hope to identify new therapeutic targets. The development of new treatments for KRAS mutant lung adenocarcinoma would be a major advance for all Kras mutant lung adenocarcinoma patients.