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. Our laboratory is focused on delineating the mechanisms by which tumor heterogeneity develops and impacts on tumor progression.
We apply fundamental developmental biology tools, such as lineage tracing, and bioinformatic approaches to study the functional consequences of tumor heterogeneity in pancreatic cancer. Our work has demonstrated a role for selective bottlenecks during the clonal evolution of pancreas cancer and suggest a role for tumor-initiating in pancreatic tumor progression. We have also identified critical pathways and interactions in tumor cells that can drive metastatic competency.
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 developed a multi-color fluorescent lineage labeled murine model of pancreas cancer (KPCX mouse). In our model, the lineage label enables identification and isolation of neoplastic cells with heterogenous metastatic properties. Through comparisons of these 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.
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.