Research Areas
1. Cancer Signaling in Tumorigenesis and Metastasis
The genesis and progression of cancer involves a series of genetic and epigenetic cellular alterations leading to aberrant mitogenic and survival signaling, as well as to the acquisition of invasive traits that promote metastasis to distant sites. Lipid second messengers such as diacylglycerol (DAG) and phosphatidylinositol-3,4,5-triphosphate (PIP3) are produced upon stimulation of membrane receptors (e.g. tyrosine-kinase receptors), and activate central signal transduction pathways linked to cell proliferation, survival and motility. Deregulated production and/or degradation of these lipid second messengers, or functional anomalies in the expression/activation status of their effectors, represent major contributing factors to malignant cell transformation and the acquisition of metastatic traits. Using state-of-the-art cellular, molecular and microscopy approaches, our laboratory identified fundamental contributions for lipid effector kinases and small G-protein regulators in prostate, breast, lung and other cancers. Protein Kinase C (PKC) isozymes and Rac-Guanine-nucleotide Exchange Factors (Rac-GEFs) were found to play key roles in the control of tumorigenic signaling pathways and transcriptional networks, thus contributing to specific steps of cancer initiation, progression and metastasis.
DAG signaling rewiring through oncogenic PKC isozymes. Adapted from: Sci. Signaling 15(729):eabo0264 (2022).
Activation of Rac-GEFs by receptor tyrosine kinases in lung adenocarcinoma cells. Adapted from: Trends Cell Biol. Oct;32(10):815-818 (2022).
https://www.sciencedirect.com/science/article/pii/S0962892422001428?via%3Dihub
2. Mouse Models of Cancer
A major area of research in our laboratory is the development of animal models aimed at deciphering 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.
PKCepsilon cooperates with loss of the PTEN tumor suppressor for prostate tumorigenesis. From: Cell Reports 19(2):375-388 (2017)
https://www.sciencedirect.com/science/article/pii/S2211124717303881?via%3Dihub
3. 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.
DAG signaling in the tumor microenvironment. From: Sci. Signaling 15(729):eabo0264 (2022).
4. 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. Exceptionally valuable information on the oncogenic and metastatic pathways leading to racial disparities in PCa.
Docking of a DAG analogue to a PKCdelta C1b domain. From: J. Med. Chem. 64(15):11418-11431 (2021)