I am a physician scientist in gastroenterology with a longstanding interest in understanding the cellular and molecular mechanism driving tumor metastasis, therapy resistance, and growth, with an emphasis on pancreatic cancer. Normal tissues and tumors are comprised of diverse cell populations with varying molecular features, giving rise to heterogeneity in both behavior and function. In tumors, this can manifest as subpopulations of cells acquiring the ability to metastasize, develop therapy resistance, or initiate tumor growth. In pancreatic cancer, cellular heterogeneity is a major contributor to poor outcomes. My laboratory applies fundamental developmental biology tools, such as lineage tracing and genetically engineered mouse models, molecular screening tools, and bioinformatic approaches to study the functional consequences of tumor heterogeneity in pancreatic cancer with the goal of translating these findings into new therapies and clinical trials.
My research training began during medical school when I was awarded the prestigious Howard Hughes Medical Institute (HHMI) Research Scholars Fellowship. During this time, I conducted research in cell and molecular biology under the guidance of Dr. Richard Siegel at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). My research focused on understanding the mechanisms by which mutations in the TNF receptor lead to immune dysfunction in the rare disorder, TNF Receptor Associated Periodic Syndrome (TRAPS).
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I am a physician scientist in gastroenterology with a longstanding interest in understanding the cellular and molecular mechanism driving tumor metastasis, therapy resistance, and growth, with an emphasis on pancreatic cancer. Normal tissues and tumors are comprised of diverse cell populations with varying molecular features, giving rise to heterogeneity in both behavior and function. In tumors, this can manifest as subpopulations of cells acquiring the ability to metastasize, develop therapy resistance, or initiate tumor growth. In pancreatic cancer, cellular heterogeneity is a major contributor to poor outcomes. My laboratory applies fundamental developmental biology tools, such as lineage tracing and genetically engineered mouse models, molecular screening tools, and bioinformatic approaches to study the functional consequences of tumor heterogeneity in pancreatic cancer with the goal of translating these findings into new therapies and clinical trials.
My research training began during medical school when I was awarded the prestigious Howard Hughes Medical Institute (HHMI) Research Scholars Fellowship. During this time, I conducted research in cell and molecular biology under the guidance of Dr. Richard Siegel at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). My research focused on understanding the mechanisms by which mutations in the TNF receptor lead to immune dysfunction in the rare disorder, TNF Receptor Associated Periodic Syndrome (TRAPS).
My initial work led to the discovery that mitochondrial reactive oxygen species (ROS) plays an important role in the pro-inflammatory phenotype of TRAPS and may function as a novel therapeutic target for TRAPS and other inflammatory diseases. This work led to a conceptual shift in our understanding of the role of ROS in TNF mediated disorders. After completion of medical school, I pursued my training in internal medicine at the Massachusetts General Hospital, followed by a Fellowship in Gastroenterology at the University of Pennsylvania through the ABIM physician-scientist pathway.
After the first year of my Gastroenterology Fellowship, I began my research fellowship training in the lab of Dr. Ben Stanger in the Division of Gastroenterology and Cancer Biology. During this time, I applied fundamental developmental biology tools, such as lineage tracing, to study the functional consequences of tumor heterogeneity in pancreatic cancer. I developed a multi-color fluorescent lineage labeled murine model of pancreas cancer – the “KPCX” mouse – to track the contribution of different pancreatic cancer cells to all stages of tumor progression. In our model, the lineage label enables identification and isolation of heterogenous tumor populations. The KPCX system represented the first autochthonous lineage labeled model of tumor heterogeneity in PDA and has provided an unprecedented window into the clonal evolution of pancreatic cancer. We demonstrated that pancreatic tumors undergo clonal reduction during tumor progression, whereby aggressive, fast-growing clones become rapidly dominant and suggest a hierarchical organization to tumor growth.
Furthermore, my work established that metastases can develop through the dissemination and seeding by heterogeneous circulating tumor cell clusters (CTC-clusters) and found that heterogeneity in the mechanisms by which tumor cells undergo epithelial-to-mesenchymal transitions (“full” or “partial” EMT) can determine if they invade as single cells or collective units. In addition, our analysis of numerous primary pancreatic tumor clones has also uncovered significant heterogeneity in metastatic rates in murine and human stage IV disease. We have identified transcriptional networks and genomic alterations associated with these heterogenous metastatic phenotypes in pancreatic cancer and are currently examining how these pro-metastatic pathways regulate metastatic competency, organotropism, and interactions with the tumor microenvironment.
My work has resulted in multiple publications, invited lectures, and grants including a CPRIT-Scholar Recruitment of First Time Tenure Track faculty award, Disease-Oriented Clinical Scholars (DOCS) award from UT Southwestern, NIH NIDDK career development award (K08), American Gastroenterological Association (AGA)-Caroline Craig Augustyn & Damian Augustyn Award in Digestive Cancer, and a NIH Paul Calabresi Career Development Award (K12).
As an independent investigator, my research program is focused on defining the mechanisms by which tumor heterogeneity develops, evolves, and influences tumor metastasis and therapy resistance in pancreatic cancer. Using novel pre-clinical tumor models and deep sequencing approaches, my lab will aim to: 1) Define genetic and microenvironmental factors that enable tumor cells to metastasize, 2) examine the role of stem-cells/tumor initialing cells in the development of PDA, and 3) integrate pre-clinical models with human sequencing datasets to enable discovery of therapeutically tractable pathways to halt tumor growth and metastasis. Ultimately my goal is to develop innovative approaches to understanding the biology of GI cancers and translating these findings to the clinical setting.
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