Christine A. Iacobuzio-Donahue: Overview
Pancreatic cancer is an ideal tumor type for such studies given metastasis is a common feature of the natural history of this disease: up to 90 percent of pancreatic cancer patients present with or eventually develop metastasis. This fact also underscores why pancreatic cancer has a five-year overall survival rate of 6 percent and illustrates the urgent medical need to understand these mechanisms and improve upon these poor survival rates.
Our laboratory is unique in that it utilizes primary and metastatic tissues obtained through post-mortem donations from cancer patients in combination with next-generation sequencing of the harvested tissues to understand the mechanisms of metastasis. This approach has led to our discovery of the distinct patterns of metastatic failure in pancreatic cancer patients, the relationship of these patterns of failure to the genetics of the primary carcinoma, the origin of distant metastases from subclonal populations that are preexistent within the primary carcinoma, and the timing of distant metastasis formation based on computational models.
The current goals for our laboratory are as follows:
First, we aim to determine the extent to which subclonal genetic evolution within a primary carcinoma selects for prosurvival phenotypes, with the consequence of these phenotypes being metastasis. For example, we are interested to know if subclonal genetic evolution generates one or more metastatic subclones within the primary site and if gene alterations that accumulate within metastatic subclones target specific core pathways. These functions/pathways may be targeted by a variety of genetic mechanisms both within different subclones in the same pancreatic carcinoma and across different patients’ carcinomas, providing a definitive basis of genetic heterogeneity in cancer. This is important to know as genetic heterogeneity is believed to be a major reason for treatment failure and yet a full understanding of heterogeneity at a fundamental level is lacking.
Second, we are studying the extent to which pro-metastatic subclones have unique morphologic, immunologic, and microenvironmental characteristics that distinguish them from other subclones within the same primary tumor. Unlike our first goal, these studies place greater emphasis on the role of the microenvironment as a selective force that favors the birth of metastasis-enabled cells.
Finally, using a combination of post-mortem tissue from a wide variety of tumor types and long-term evolution studies, we aim to determine the dynamics of Darwinian selection of human cancer cells in real time, with the goal of identifying translational and therapeutic opportunities for patients.