Cancer Signaling in Tumorigenesis and Metastasis

Our laboratory studies the contribution of PKC isozymes, small GTPases and their regulators to oncogenesis and metastatic dissemination of cancer cells. Key areas of interest include the regulation of mitogenic signaling, transcriptional networks, and epithelial-to-mesenchymal transition (EMT). Another important area of interest is the formatioan of actin-rich membrane protrusions (ruffles, lamellipodia, tunneling nanotubes) via PKC and small G-protein pathways, and their contribution to cancer cell growth, motility and invasiveness. We identified major associations between aberrant expression/activity of these signaling proteins and the progression of different types of prostate, lung, breast and other cancers.

Mouse Models of Cancer

We developed animal models to dissect the roles of PKC isozymes and Rac-GEFs in tumorigenesis and metastasis. Genetically-engineered mouse models generated in our laboratory were instrumental to establish the contribution of oncogenic PKCepsilon in the cancer initiation and progression, as well as to establish functional associations with oncogenes (such as KRAS) and tumor suppressors (such as PTEN). We are extending these studies to other members of the PKC family to understand their roles in prostate and lung cancer. The generation of lung-specific Rac-GEF-deficient models using CRISPR-based editing will be instrumental to dissect their roles in lung cancer tumorigenesis and metastasis.

Tumor Microenvironment and the Immune Landscape

Tumor growth is anarchically regulated by the interplay between cancer cells and the tumor microenvironment (TME). DAG-regulated effectors are restricted not only to cancer cells but also to noncancerous cells in the TME, potentially playing a dynamic relationship between cancer cells and tumor immune cells that coalesce to shape tumor growth and therapy responses. Our goal is to investigate the relevance of aberrant cancer cell DAG signaling in the control of the immune landscape, and determining whether it influences the immune cell populations that contribute to tumor elimination. Dissecting the involvement of PKC isozymes in the production of cytokines acting as modifiers of the TME as well as in the expression of immune checkpoint proteins will help dissecting cellular crosswalks within the tumor milieu, and hopefully pave the way to novel antitumor therapeutic approaches.

Translational Therapeutics and Health Disparities

Discerning the complex signal transduction pathways regulated by lipid second messengers in cancer cells would provide the foundation for novel therapeutic strategies. Molecular and genetic means have been used in our laboratory to set proof-of-principle for the contribution of DAG effectors and Rac-GEFs to cancer progression. Collaborative efforts are underway to better understand the structural principles regulating the activation of these signaling molecules and design of chemical agents capable of interfering with their aberrant activation in cancer. Ongoing efforts are also being pursued to dissect differences in expression and activation of these pathways as underlying causes for racial disparities in cancer, e.g. prostate cancer, which occurs with greater incidence and aggressiveness in the African American population.