Christina M. Ferrer, PhD

University of Central Florida, BS, Biological Sciences, 2007

Barry University, MS, Biomedical Sciences, 2009

Drexel University College of Medicine, PhD, Molecular and Cell Biology & Genetics, 2015

Massachusetts General Hospital Cancer Center and Harvard Medical School, Postdoctoral Study, 2020

Massachusetts General Hospital Cancer Center and Harvard Medical School, Instructor in Medicine, 2022

I have a broad background in cancer cell biology, signaling, and mechanisms and models of cancer with a focus on the mechanisms driving metastasis. For my PhD thesis work, in the spring of 2011, I joined the laboratory of Dr. Mauricio Reginato, where I studied oncogenic alterations that drive metabolic reprogramming in cancer. My thesis work focused on deciphering the molecular mechanisms through which OGT and O-GlcNAcylation contribute to cancer phenotypes, including metabolic reprogramming, survival and metastasis. Using metabolomic profiling, I demonstrated that reducing O-GlcNAcylation in cancer cells decreases metabolic pathways associated with a shift in glycolysis through regulating stability of the transcription factor HIF-1α. My thesis work further identified a novel molecular pathway linking O-GlcNAcylation to invasion and metastasis via regulation of the longevity-associated protein SIRT1. Throughout my PhD studies I developed a strong conceptual and technical foundation in cancer biology as well as a deep interest in understanding epigenetic mechanisms as they relate to cancer metastasis.

During my postdoctoral training in the Mostoslavsky laboratory, I had the opportunity to contribute to our understanding of how chromatin dynamics influences cellular and disease processes, by studying the role of the NAD+ dependent histone deacetylase SIRT6 in regulating metabolism, development, and tumor progression. My initial studies identified a germline mutation in the histone deacetylase SIRT6 as a cause for fetal demise. These studies not only defined SIRT6 as a key factor in human development, but also represent the first description of chromatin factor mutation as a driver of a human syndrome of perinatal lethality. In executing these studies, I gained expertise in developmental and stem cell biology which has proven to be invaluable in my current studies related to cancer metastasis.

Throughout my late postdoctoral career and in the transition to independence, I continued studying cancer metastasis in the context of identifying epigenetic adaptations that are unique to established metastatic tumors, particularly in pancreatic cancer. Many pancreatic cancer (PDA) patients present with synchronous metastatic disease at the time of diagnosis with a primary tumor; many of which lack metastasis-specific driver mutations. I developed a loss-of-function shRNA targeted screen in metastatic-derived cells and identified the glutathione S-transferase Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for metastasis and dispensable for primary tumor growth. I have identified Gstt1 as both dispensable for primary tumor growth and required for dissemination and metastatic maintenance. In metastatic lesions, Gstt1 contributes to both intratumoral and intertumoral heterogeneity through regulation of proliferation, EMT and extracellular matrix organization through glutathionylation of intracellular Fibronectin in a subpopulation of Gstt1^high metastatic cells (Ferrer et al, BioRxiv, 2022). This project has been funded by an NIH K99/R00 Pathway to Independence Award aiming to understand the role of Gstt1 in metastatic lesions, which will serve as the basis for my own independent research program and will provide important preclinical demonstration as to whether Gstt1 and its downstream targets are required for sustained growth of metastatic tumors. These studies will significantly contribute to the field in understanding unique vulnerabilities of metastatic pancreatic cancer and provide a possible therapeutic window for the treatment of a subset of patients with metastatic disease.

My long-term goals are to further study the role of Gstt1 in metastatic chemoresistance, and to determine the influence of the Gstt1^high population on the metastatic immune microenvironment. I will also characterize the role of other novel epigenetically-regulated mediators of metastasis previously identified in our screen to be important for metastatic maintenance and cell growth. These studies will provide 1) further characterization of a novel cell population involved in metastatic maintenance, 2) explore new avenues to exploit immune-mediated clearance in the treatment of pancreatic metastasis, 3) define Gstt1 as a key driver of chemoresistance in metastasis and 4) identify novel mediators of metastatic dissemination, colonization and outgrowth. My overall research program will be critical in advancing our understanding of the mechanisms governing metastatic growth and while maintaining a commitment to teaching, mentoring and establishing a culture of diversity and inclusion in my laboratory and within the institution.

cancer metastasis, pancreatic cancer, metastasis-initiating cells, dissemination, pancreatic cancer metastasis

Ferrer, C. M., Lynch, T. P., Sodi, V., Falcone, J. N., Schwab, L., Peacock, D., Vocadlo, D.J., Seagroves, T. N., and Reginato, M. J. Nutrient sensor O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of HIF-1 pathway. Molecular Cell (2014) Jun 5;54(5):820-31.

Ferrer, C. M. and Reginato, M. J. Cancer Metabolism: Crosstalk between Signaling and O-GlcNAcylation; InCancer Genomics and Proteomics: Methods and Protocols; Narendra Wajapeyee (Editor). Humana Press; (2014) vol. 1176,2nd ed, XII, 304 p.

Ferrer, C. M., and Reginato, M. J. Sticking to Sugars at the Metastatic Site: Sialyltransferase ST6GalNAc2 acts as Breast Cancer Metastasis Suppressor. Cancer Discovery (2014) Mar; 4(3):275-7.

Ferrer, C. M., and Reginato, M. J. Sweet Connections: O-GlcNAcylation links cancer metabolism and survival. Molecular & Cellular Oncology (2015) Jan-Mar; 2(1): e961809.

Ferrer, C. M., Lu, T. Sinclair, D. A., and Reginato, M. J. O-GlcNAcylation regulates cancer cell invasion via the NAD+-dependent longevity protein SIRT1. Oncogene (2016) Jan 26;36(4):559-569.

Ferrer, C.M., Sodi, V.L., and Reginato, M. J. O-GlcNAcylation in Cancer Biology: Linking Metabolism and Signaling. Journal of Molecular Biology (2016) Aug 14;428(16):3282-3294.

Ferrer, C.M.*, Alders, M. *, Postma, A.V. *, Park, S., Klein, M.A., Pajkrt, E., Glas, A., van Koningsbruggen, S., Christoffels, V.M., Mannens, M.A.M., M., Knegt, L., Etchegaray, J.P., Denu, J.M., Mostoslavsky, G., van Maarle, M.C., Mostoslavsky, R. An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. Genes & Development (2018) Mar 1;32(5-6):373-388. (cover image featured in issue).

Ferrer, C.M., Boon, R., Cho, H., Bernasocchi T., Wong, L.P., Cetinbas, M., Haggerty, E.R., McLoughlin, D.E., Sadreyev, R.I., Juric, D., Mostoslavsky, R. The glutathione S-transferase, Gstt1 is a robust driver of survival and dissemination in metastases. BioRxiv (2022) (under review).