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.