Extracellular Matrix Receptor in Pancreatic Cancer Growth and Metastasis

Abstract public domain (NIH RePORTER)

Project Summary/Abstract: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with the lowest 5-year survival rate among all major cancers. Adenosquamous carcinoma of the pancreas (ASCP) is a subtype of PDAC with the worst clinical outcome and higher a metastatic potential. Currently, very little is known about the molecular pathogenesis and vulnerabilities in ASCP. A growing number of studies indicate that a substantially higher fraction of conventional PDAC harbors admixed adenosquamous features than was previously recognized, which indicates that a potentially significant fraction of pancreatic cancers may not have been correctly characterized and treated as one disease. This highlights the need for a better understanding of ASCP with the development of better models that can enable us to study the biological basis of initiation, and progression of this disease. The primary goal of this proposal is to understand the molecular mechanisms contributing to the growth and metastasis of pancreatic adenosquamous tumors that may be leveraged to develop effective therapies for the treatment of this disease. My prior work, based on a novel mouse model of adenosquamous carcinoma, shows that the expression of an extracellular matrix receptor- hyaluronan-mediated motility receptor (HMMR) gradually increases with the progression of the disease and is required for the growth of the primary pancreatic squamous tumor cells. Tumor-specific HMMR also controls tumor cell-extrinsic processes such as angiogenesis and fibrosis in shaping tumor microenvironment (TME). Moreover, HMMR expression in human adenosquamous cancer promotes mesenchymal phenotype, which is considered an important early prerequisite for metastasis. Based on our findings I hypothesize that HMMR plays an important role in the growth and metastasis of pancreatic adenosquamous cancers by regulating tumor cell-intrinsic and extrinsic factors. To test my general hypothesis, I propose the following two specific aims: (1) determine the mechanisms by which HMMR promotes the growth and migration of pancreatic cancer cells, and (2) determine if HMMR is required for pancreatic cancer metastasis, and. In summary, my proposed study will define the mechanisms how HMMR serves as a critical factor in the growth and distant metastasis of pancreatic cancers. This knowledge may help establish HMMR as a novel target for the effective therapy of this challenging disease. Additionally, this study will provide the conceptual groundwork and preliminary data for a competitive R01 submission, that could help me launch my independent career.

Public health relevance public domain (NIH RePORTER)

Project Narrative: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a dismal prognosis, in which the adenosquamous subtype has the lowest survival rate of all subtypes. The current proposal seeks to deeply understand the mechanistic role of unconventional extracellular matrix receptor- HMMR (hyaluronan-mediated motility receptor) in the growth and metastasis of pancreatic adenosquamous cancer. The knowledge established from this work could provide important information that could be critical for the development of new treatment strategies and improved patient outcomes.