Friday, May 9, 2025
5/9/2025
Unraveling the functional contribution of extracellular vesicles in pancreatic cancer - PROJECT SUMMARY/ABSTRACT Despite major advances in cancer treatment over the last 20 years, metastatic pancreatic adenocarcinoma (PDAC) remains largely unresponsive to treatment. Signaling between cancer cells and the surrounding host tissue microenvironment (TME) is a critical regulator of tumor progression and metastasis, but an incomplete understanding of these interactions has hindered therapeutic targeting. Recent studies have identified extracellular vesicles (EVs) as potential mediators of intercellular communication to regulate cancer progression and metastasis. As a result, targeting EV transfer and/or the downstream effects of such transfer may provide therapeutic benefits; however, an understanding of the precise mechanisms of EV release and entry into target cells, and the functional consequences of EV exchange in vivo is urgently needed. Here, I will test the central hypothesis that cancer cell EVs modulate the tumor microenvironment to facilitate PDAC progression and metastasis. I will use novel genetically engineered mouse models to track and determine the functional impact of cancer cell EV (ccEV) transfer on the local and metastatic TMEs to alter PDAC initiation, progression, and metastasis. This will be accomplished through 3 Aims: (1) to investigate the functional contribution of ccEVs in PDAC initiation and progression, (2) to evaluate the functional contribution of ccEV release and CD47 on the surface of ccEVs in liver metastasis, and (3) to identify the role of mutant Trp53 and novel EV mediators of stromal reprogramming to facilitate liver metastasis. The proposed research program combined with additional research and career development skills training will enable me to launch my independent research career. I will be committed to expanding my networking, mentoring, leadership, lab management, and scientific communication skills, and I have assembled an advisory committee consisting of Dr. Ronald DePinho, Dr. Anirban Maitra, and Dr. Elizabeth Shpall to provide input and guidance on my career development. Altogether, this K22 award will help me accomplish my long-term goal of understanding the mechanisms of intercellular communication between cancer cells and the microenvironment to facilitate pancreatic cancer initiation, progression, and metastasis in order to identify novel therapeutic vulnerabilities.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).