Desmoid tumors (DTs) are mesenchymal tumors that occur sporadically or in the context familial adenomatous polyposis (FAP). Although rare in the general population, DTs are a leading cause of death in FAP patients. There is no effective cure for patients with unresectable disease, and little is known about the molecular biology driving desmoid tumorigenesis. Our laboratory seeks to characterize the biological requirements necessary for DT formation and identify targeted therapies for this disease. Currently, we are investigating the role of hyaluronic acid (HA) in driving desmoid proliferation and have preliminary evidence that HA is an abundant constituent of DTs.
Based on our novel observations, we hypothesize that hyaluronic acid plays a critical role in desmoid tumorigenesis and provides a novel target for therapy. Furthermore, we propose that HA promotes DT progression through crosstalk with inflammatory components of the tumor microenvironment such as mesenchymal stem cells (MSCs). We will test this hypothesis through two specific and independent aims:
Aim 1: To evaluate the anti-tumorigenic effects of hyaluronic acid inhibition in human desmoid-derived cells. Aim 2: To evaluate the anti-tumorigenic effects of hyaluronic acid inhibition in the Apc1638N mouse and xenograft models. Our findings will 1) address major gaps in our current understanding of DT pathophysiology, 2) define the role that HA plays in driving desmoid tumorigenesis, and 3) identify novel targets for therapy. As a clinical referral center for patients with DTs, we are uniquely situated to carry out this proposal given our access to rare patient tumors that will sustain our future work and allow us to expeditiously translate benchside discoveries to clinical trials.