Friday, September 22, 2023
9/22/2023
PROJECT SUMMARY/ABSTRACT Though oncogenes are often prioritized as the primary drivers of cancer, tumor heterogeneity is widely acknowledged for its critical contributions to microenvironment adaptation, chemoresistance, and metastasis. In the cancer stem cell model, cells with self-renewal capacity give rise to diverse, transit-amplifying progeny to maintain tumor heterogeneity. These self-renewing cells are enriched for tumor-forming capacity in orthotopic transplantation assays and display properties such as delayed cell cycle progression, progenitor-like gene expression programs, and enhanced ex vivo sphere forming capacity. However, their identification has proven challenging in the absence of well-characterized stem cell markers such as those found in the hematopoietic and intestinal lineages. An additional challenge is highlighted by the recent understanding that self-renewal capacity can be acquired by more “differentiated” cells which appropriate developmental pathways in a cell- type specific manner. Thus, there is an urgent need to identify reliance of cancers on such self-renewal pathways as potential therapeutic targets. Using our oncogenic Kras- p53 mutant mouse model, we previously identified a series of surface markers (CD24+, ITGB4+, Notch-high) that enriched for tumor propagating capacity in serial orthotopic transplantation and ex vivo sphere formation assays. We discovered a unique requirement for Notch3 in primary tumor cells and showed that their proliferation requires activated Notch signaling. Thus, I propose to study the contribution of Notch in lung tumor development, and I hypothesize that Notch3 is required to maintain a self-renewal state in this context. Specifically, I will (1) use a lineage-tracing model to define the in situ niche and fate of permanently labeled Notch3-expressing cells and their progeny over tumor progression, and (2) identify the downstream targets of the activated Notch3 intracellular signaling in the lung cancer context. Results from these aims will provide insight into the role of Notch3 expression in tumor development and elucidate the molecular mechanisms regulated by the Notch pathway, whose relevance to lung cancer is further nominated by its well-studied role as a fate determinant in lung development. Therefore, this work has the potential to discover self-renewal paradigms required for both normal and oncogene-driven development in a lung-specific manner. As outlined in my fellowship training plan, I will undertake these aims under the supervision of Dr. Alejandro Sweet-Cordero, a well-recognized expert in the use of these genetically engineered mouse models. His lab is based at UCSF, one of the leading institutions in clinical care and translational research, and belongs to an extensive network of cancer biology labs and collaborators. My training plan incorporates rigorous scientific training of in vivo tumor modeling and bioinformatics analysis with mentorship from experts in these respective fields, longitudinal clinical experience, and specific professional development opportunities. Overall, completion of this proposal will support my career as a successful physician-scientist in the field of cancer biology.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
