2021 Nikki Mitchell Foundation Seed Grant Winner

Significance of Research: Pancreatic adenocarcinoma (PDAC) mortality is mostly due to an overwhelming metastatic burden 1–4. This underscores two biologic challenges of PDAC: (1) resistance to anti-proliferative therapies, and (2) progressive dissemination with resultant metastatic lesions. These challenges are a result of cell populations programmed for stemness, invasion and metastasis. Programming for these lethal hallmarks of cancer is facilitated by a pro-metastatic tumor microenvironment. We recently discovered that PDAC has tumor microenvironment of metastasis (TMEM) doorways which are portals for intravasation in other cancers, and implicated in supporting a pro-metastatic niche 5,6. We propose to use a combination of immunohistochemistry (IHC) and immunoflourescence (IF) to detect PDAC cells with pro-metastatic properties in human and mouse PDAC specimens and determine their spatial relationships to TMEM doorways. This research will establish TMEM doorways as a targetable mechanism of metastasis and treatment resistance in PDAC. Critically, we are actively studying Tie2 inhibitors as a means of disrupting the TMEM doorway mediated pro-metastatic niche in other tumor types and anticipate, on the basis of our preliminary results, that they will function similarly in PDAC. Results from this project will provide the rationale to evaluate the efficacy of combining TMEM doorway targeting to contemporary chemotherapy. Our research team harnesses our physician-scientist expertise in surgical oncology (McAuliffe), and pathology (Panarelli) to better understand PDAC resistance and metastasis. Proposed studies leverage established mouse models and analysis of human specimens. Given the advanced state of development of relevant inhibitors, we are poised to translate these discoveries immediately into clinical trials.