Over half of all human cancers consist of alterations in the p53 tumor suppressor gene. In normal healthy cells, p53 responds to stress stimuli by regulating the expression of downstream target genes that bring about various cellular outcomes (Fig.1). On the flip side of the coin, the regulation of these tumor suppressor genes is disrupted by mutations in p53, the vast majority of which are missense and localize to its DNA binding domain. Mutant p53 proteins (mutp53) lose tumor suppressor function and can also exhibit novel gain-of-function (GOF) activities that promote additional growth advantages over cells that lack p53. While mutp53 is an attractive target for cancer therapy, an understanding of the mechanisms underlying mutp53 regulation and function are needed before this oncogene can be exploited for therapeutic benefit. Toward this goal, I have developed a multidisciplinary research program to advance our understanding of the cellular and molecular mechanisms underlying the loss of function and GOF properties of mutp53. Our parallel lines of investigation aim to address the questions outlined below and ultimately promote human health through the identification of molecular vulnerabilities in mutp53 cancers that can serve as new biomarkers or therapies in precision medicine.
Our research program utilizes a combination of approaches that include cutting-edge high-throughput NGS technologies, state of the art microscopy techniques, quantitative proteomics, biochemistry, and cell-based/genetic assays. We also employ powerful cell-free assays (consisting of >97 polypeptides) that fully reconstitute transcription on chromatin templates and are powerful in discerning direct (causal) effects of epigenetic and transcriptional regulatory mechanisms. More recently, we have established patient-derived colorectal tumor organoids (PDTO) co-cultured with immune cells to investigate how the crosstalk between mutp53-expressing tumor cells and immune cells contribute to metastatic phenotypes.