Maria Soledad Sosa, PhD
- ASSISTANT PROFESSOR | Medicine, Hematology and Medical Oncology
My undergraduate training consisted in the study of melanoma biology, in the laboratory of Osvaldo Podhajcer at the renowned Leloir Institute where I focused in the identification of novel melanoma signaling targets using proteomics. From this training phase I published a very complete story in Proteomics (Sosa MS, et al., Proteomics 2007). My Ph.D. training program was carried out at the University of Pennsylvania in a joint program with the University of Buenos Aires. This training was under the mentorship of Dr. Marcelo Kazanietz, a well-recognized scientist in cell signaling studies in prostate and breast cancer. During this time I focused on the study of P-Rex1, a Rac-GEF protein, and how this factor contributes to the malignancy of mammary tumor cells. We demonstrated that P-Rex1 is important for migration and tumor development of breast cancer cells (Sosa MS, et al., Mol. Cell 2010). In 2010, I joined Dr. Julio Aguirre-Ghiso laboratory and since then I have been working in understand how tumor cell dormancy is established once tumor cell disseminate to secondary organs. In this work I was able to link the orphan nuclear receptor NR2F1 to a novel function during tumor cell dormancy (Sosa et.al. Nat. Com 2015). I found that NR2F1 is required for malignant cells to undergo dormancy and it does this by upregulating the expression of cell cycle inhibitors and decreasing cyclin D1 levels. I also found that NR2F1 induces the mRNA levels of NANOG, SOX2 and OCT-4 in dormant cells. The latter result is surprising and important since it is the first time that a connection between self-renewal genes and quiescence programs has been established in tumor cells and dormancy. In 2012 I was awarded a DoD Breast Cancer Postdoctoral Grant to study the processes responsible for dissemination and target organ colonization by breast tumor cells. In 2015 I was promoted to Assistant Professor position in the Department of Medicine, Icahn School of medicine at Mount Sinai.
PhD, University of Buenos Aires/University of Pennsylvania
Targeting Minimal Residual Disease
I am interested in explore the intrinsic and extrinsic signaling pathways that allow the establishment and maintenance of minimal residual disease in cancer patients. I found that NR2F1 while lost in primary tumors is re-expressed upon surgical removal of the primary tumor in local and distant residual tumor cells and allows them to undergo dormancy. Importantly, I was able to demonstrate the re-expression of NR2F1 in dormant disseminated tumor cells (DTCs) derived from prostate cancer patients. This dormancy phase regulated by NR2F1 involved upregulation of cell cycle inhibitors and interestingly it also required the induction of stem cell genes. The latter result is surprising and important since it is the first time that a connection between pluripotency genes and quiescence programs has been established in tumor cells and dormancy. In addition, I also found a novel function for NR2F1 in regulating histone modifications during dormancy. These findings open a new field of investigation where epigenetics modulations may be responsible for the quiescence phase of minimal residual disease. In addition I developed a screening strategy to find agonists and antagonists of NR2F1 required for disseminated tumor cell reprogramming into dormancy. This work already identified molecules with these activities that we are optimizing. Importantly this work has been selected for a potential spin-off via the Accelerator program that Eli Lilly and other companies in NYC have in place.
Early Dessimination Events in Breast Cancer
In 2012 I was awarded a DoD Breast Cancer Postdoctoral Grant to study the processes responsible for dissemination and target organ colonization by breast tumor cells. I found that before pre-malignant lesions can form a primary tumor they are constantly releasing cells into the blood stream and these pre-malignant DTCs although quiescent at the beginning could eventually proliferate into metastases at secondary sites. These pre-malignant cells may constitute, by themselves and/or in cooperation with later arriving DTCs, the sources of relapses. Thus, my future research will aim to understand how these cells very early in tumor progression disseminate, survive and cooperate with the microenvironment to form metastases. This program will strongly impact the way modern therapy is achieved and it will incorporate a new biology in metastasis disease.
Sosa MS, Parikh F, Maia AG, Estrada Y, Bosch A, Bragado P, Ekpin E, George A, Zheng Y, Lam HM, Morrissey C, Chung CY, Farias EF, Bernstein E, Aguirre-Ghiso JA. NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes. Nature communications 2015; 6.
Sosa MS, Bragado P, Aguirre-Ghiso JA. Mechanisms of disseminated cancer cell dormancy: an awakening field. Nature reviews. Cancer 2014 Sep; 14(9).
Aguirre-Ghiso JA, Bragado P, Sosa MS. Metastasis awakening: targeting dormant cancer. Nature medicine 2013 Mar; 19(3).
Begley U, Sosa MS, Avivar-Valderas A, Patil A, Endres L, Estrada Y, Chan CT, Su D, Dedon PC, Aguirre-Ghiso JA, Begley T. A human tRNA methyltransferase 9-like protein prevents tumour growth by regulating LIN9 and HIF1-α. EMBO molecular medicine 2013 Mar; 5(3).
Curtis JJ, Walls JT, Schmaltz RA, Boley T, Landreneau R, Nawarawong W. Prognosis of hospital survivors after salvage from cardiopulmonary bypass with centrifugal cardiac assist. ASAIO transactions / American Society for Artificial Internal Organs; 36(3).
Bragado P, Estrada Y, Sosa MS, Avivar-Valderas A, Cannan D, Genden E, Teng M, Ranganathan AC, Wen HC, Kapoor A, Bernstein E, Aguirre-Ghiso JA. Analysis of marker-defined HNSCC subpopulations reveals a dynamic regulation of tumor initiating properties. PloS one 2012; 7(1).
Kim RS, Avivar-Valderas A, Estrada Y, Bragado P, Sosa MS, Aguirre-Ghiso JA, Segall JE. Dormancy signatures and metastasis in estrogen receptor positive and negative breast cancer. PloS one 2012; 7(4).
Wertheimer E, Gutierrez-Uzquiza A, Rosemblit C, Lopez-Haber C, Sosa MS, Kazanietz MG. Rac signaling in breast cancer: a tale of GEFs and GAPs. Cellular signalling 2012 Feb; 24(2).
Sosa MS, Avivar-Valderas A, Bragado P, Wen HC, Aguirre-Ghiso JA. ERK1/2 and p38α/β signaling in tumor cell quiescence: opportunities to control dormant residual disease. Clinical cancer research : an official journal of the American Association for Cancer Research 2011 Sep; 17(18).
Wen HC, Avivar-Valderas A, Sosa MS, Girnius N, Farias EF, Davis RJ, Aguirre-Ghiso JA. p38α Signaling Induces Anoikis and Lumen Formation During Mammary Morphogenesis. Science signaling 2011; 4(174).
Sosa MS, Lopez-Haber C, Yang C, Wang H, Lemmon MA, Busillo JM, Luo J, Benovic JL, Klein-Szanto A, Yagi H, Gutkind JS, Parsons RE, Kazanietz MG. Identification of the Rac-GEF P-Rex1 as an essential mediator of ErbB signaling in breast cancer. Molecular cell 2010 Dec; 40(6).
Griner EM, Caino MC, Sosa MS, Colón-González F, Chalmers MJ, Mischak H, Kazanietz MG. A novel cross-talk in diacylglycerol signaling: the Rac-GAP beta2-chimaerin is negatively regulated by protein kinase Cdelta-mediated phosphorylation. The Journal of biological chemistry 2010 May; 285(22).
Sosa MS, Lewin NE, Choi SH, Blumberg PM, Kazanietz MG. Biochemical characterization of hyperactive beta2-chimaerin mutants revealed an enhanced exposure of C1 and Rac-GAP domains. Biochemistry 2009 Sep; 48(34).
Sosa MS, Girotti MR, Salvatierra E, Prada F, de Olmo JA, Gallango SJ, Albar JP, Podhajcer OL, Llera AS. Proteomic analysis identified N-cadherin, clusterin, and HSP27 as mediators of SPARC (secreted protein, acidic and rich in cysteines) activity in melanoma cells. Proteomics 2007 Nov; 7(22).