Cancer Stem Cells & Tumor Heterogeneity

We previously identified a rare subpopulation of tumor cells characterized by surface expression of CD24+/ITGB4+/Notch3+. We have shown that these cells have increased CSC-like characteristics in both the KRASLSLG12D model and in KRASLSLG12D;p53-/- mice. In addition, the percentage of these cells as a fraction of the bulk tumor increases after repeated doses of chemotherapy, suggesting that these cells are intrinsically chemoresistant. These studies (Zheng et al, Cancer Cell 2013).

Our current efforts are directed at understanding the role of Notch3 in TPCs both in mouse models of lung cancer and in human lung cancer PDX models.  We hypothesize that understanding how Notch3 signals may help identify novel approaches to therapy for NSCLC. We are also extending our initial characterization of TPCs in the KRASLSLG12D;p53-/- to other genetic backgrounds (loss of LKB1, loss of KEAP1, etc). Using advanced reporter assays and single-cell sequencing assays, we are also trying to further understand how intratumor heterogeneity evolves over time and how it is influenced by genetic context.   

Tumor heterogeneity can occur not only within tumor cells but also with regards to the tumor stroma.  We previously identified a role for cancer-associated fibroblasts (CAFs) in promoting tumor development in both mouse and human lung cancer  (Vicent et al, Cancer Research 2012). This work has led to a collaboration with a bioengineer at Stanford (Dr. Jennifer Cochran lab) with the goal of developing therapeutic strategies to block the interaction between CAF-expressed cytokines and their receptors on tumor cells.