Tumors are complex eco-systems comprised of diverse cell populations including tumor, immune, and stromal cells. This heterogeneity in tumors results from evolutionary processes that occur during all stages of tumor formation, often resulting in the emergence of metastasis and therapeutic resistance, which are critical barriers to treatment. This is especially relevant to pancreatic cancer, where most patients present with metastasis at diagnosis and have a 5-year survival under 10%. Thus, understanding the mechanisms driving tumor evolution and the role of tumor heterogeneity in metastasis and therapy response will be important for developing new treatments and improving patient survival. Our laboratory is focused on delineating the mechanisms by which tumor heterogeneity develops and impacts on tumor progression. We apply novel pre-clinical models combined with patient derived tissues and bioinformatic approaches to study the functional consequences of tumor heterogeneity in pancreatic cancer and develop novel therapies. Furthermore, these mechanistic insights, experimental approaches, and translational applications can be extrapolated to other cancers.
Modeling Tumor heterogeneity
A major barrier to understanding the consequences of cellular heterogeneity in pancreas cancer is the lack of model systems that can capture the behavior of diverse cell populations in vivo. For example, the inability to isolate and analyze distinct metastatic populations in tumors has limited our ability to identify and target pathways that my drive metastasis. To address this major limitation, we developed a preclinical murine model system that allows us to directly track the fate of different tumor populations and examine their contributions to metastasis. In this model we engineer pancreas cells in mice to acquire mutations in Kras and P53 and at the same time these mutated cells also recombine a fluorescent reporter system which randomly labels them with one of four different fluorescent proteins. And if these cells go on to become tumors, they carry this lineage label and we can identify them using fluorescent microscopy and track their contribution to metastasis. Using this system, we established several key principles of how tumor cells migrate and evolve. We showed that tumor cells can enter the circulation as single cells or clusters of cells with the latter having higher metastatic potential. In addition, upon arrival to a distant organ, metastasis grow and evolve differently depending on which organ they are found in, suggesting that there are unique site-specific adaptations of tumor cells to their new host environment. Building on these findings and novel approaches our lab has several major ongoing projects.
Drivers of metastasis in pancreatic cancer
One of the main drivers of poor prognosis in pancreatic cancer is the presence of metastatic disease at the time of diagnosis. This results from the dissemination of a small subset of highly malignant cells within the tumor. To understand the mechanisms driving metastasis and identify therapeutic opportunities, we utilize our multi-color fluorescent lineage labeled murine model of pancreas cancer (KPCX mouse) to identify and isolate neoplastic cells with heterogenous metastatic properties. Through comparisons of metastatic cells to their paired primary tumor populations, we have identified novel transcriptional networks (coding and non-coding) and genomic alterations associated with metastatic phenotypes in pancreatic cancer. We are currently examining how these pro-metastatic pathways regulate metastatic competency, organotropism, and interactions with the tumor microenvironment.
Understanding how the Tumor Immune Microenvironment (TiME) drives metastasis
Immune cells comprise the largest population of cells in pancreatic tumors. Crosstalk between the immune and the tumor cells generates an immunosuppressive environment that contributes to metastatic progression. In our recent work, we discovered that genetic alterations of Myc in tumor cells mediate a pro-metastatic phenotype through the recruitment and alteration of tumor associated macrophages (TAMs). This occurs by the action of various secreted factors, which can be inhibited to halt metastasis formation. By combining in vivo model systems with tissue-engineering and multi-omics based approaches we are focused on understanding how tumor derived secreted factors alter the biology of TAMs and identify methods to reverse the process to enhance immune therapy.
Clonal Evolution and cellular heterogeneity in pancreatic cancer
In both tumors and regenerating tissues, subsets of cells that have acquired stem-like properties can drive tissue growth and establish the cellular heterogeneity within a tumor. Identifying these rare cell populations and determining the mechanisms by which they contribute to tissue and tumor growth is critical to developing therapies that can enhance tissue regeneration or halt tumor progression. Our laboratory has examined the clonal growth patterns of mutated pancreatic cells in vivo and 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. We are currently examining the molecular process underlying these modes of growth during the various stages of tumor initiation, metastatic progression, and in response to chemotherapy.
Ravi Maddipati | Department of internal medicine
6000 Harry Hines Blvd., NB8.221
Dallas, Tx 75390
UTSouthwestern Medical Center