Personal History:I completed my undergraduate work at Franklin and Marshall College in 1995, obtained my M.S. in 1999 and my Ph.D. in 2004 from University of Maryland Baltimore. For my thesis work, I studied the transcription factor RUNX2 and its function in angiogenesis and tumorigenesis. During my postdoctoral training with Dr. Kurtis Bachman, I learned powerful genetic techniques to develop a novel in vitro isogenic cell system for examining PTEN deficiency on cell signaling. I continued my postdoctoral training with Dr. Stuart Martin and focused on the role that PTEN deletion plays in the formation of microtentacles (McTNs) and the ability of cancer cells to metastasize. In 2012, I became a Research Associate in the laboratory of Dr. Martin.
Research Interests:Role of PTEN in microtentacle formation and metastasis
The loss of the tumor suppressor PTEN is associated with cancer stage, lymph node status, and disease-related death, and the high rate of loss in primary tumors suggests a potential role in initiation and/or progression of the disease. However, specific cellular alterations in human breast epithelium controlled by PTEN inactivation, which lead to an increased metastatic phenotype, remain poorly defined. Using a PTEN isogenic somatic cell knock-out model, we are investigating the molecular mechanisms by which PTEN loss promotes metastatic efficiency of circulating tumor cells. We have determined that PTEN loss confers both apoptotic resistance and production of microtentacles (McTNs) in mammary epithelial cells upon detachment. McTNs are membrane structures observed in detached cells and are increased in frequency, and number and length per cell as compared to their isogenic, PTEN expressing parental counterparts. These novel structures (McTNs) are structurally distinct from classical actin based extensions of adherent cells, persist for days in breast tumor lines that are resistant to anoikis, and aid in the reattachment to matrix or cell monolayers. Therefore, the combination of apoptotic resistance and enhanced McTNs expression due to PTEN loss may have important consequences for facilitating tumor cell extravasation and efficient adherence to new sites.
Are PIK3CA activating mutations and PTEN loss reciprocal mutations?
The acquisition of PIK3CA mutations and PTEN loss are often assumed to be reciprocal mutations since they can be mutually exclusive and each promotes AKT activation. However, recent clinical studies highlight major differences in patient outcomes when PTEN loss/mutation or PIK3CA mutation occurs, where PTEN loss leads to a worse patient prognosis, perhaps due to functions of PTEN beyond that of PI3K pathway maintenance. We have determined differences in cytoskeletal structure and signaling between cells with PTEN loss and PIK3CA activation, and therefore the current PI3K inhibitor therapies in clinical trials may not be sufficient for patients with PTEN loss. Understanding the molecular targets of PTEN that promote McTNs and reattachment could provide new therapeutic opportunities to reduce metastatic potential. Once substrates of PTEN are known, the kinases responsible for their phosphorylation could be targeted therapeutically. Presumably, the high level of phosphorylation in these PTEN substrates is what drives cytoskeletal alterations in PTEN-/- tumor cells.
NCI Mentored Scientist Research Award
PTEN loss increases efficiency of breast tumor metastasis
American Cancer Society Institutional Research Grant
Differential effects of PI3K and PTEN on metastatic potential
1. Charpentier, M.S., Whipple, R.A., Vitolo, M.I., Boggs, A.E., Slovic, J., Thompson, K.N., Bhandary, L., and Martin, S.S. (2013) Curcumin targets breast cancer stem-like cells with microtentacles that persist in mammospheres and promote attachment. Cancer Research. 2014 Feb 15;74(4):1250-60. PMCID: PMC3990412