Collagen I is the effective therapeutic target for treating desmoid tumors

Abstract

Desmoid tumors, known as aggressive fibromatosis, are derived from connective tissues, and local invasion is usually observed. Despite intensive efforts have been performed to investigate the novel anticancer agents in desmoid tumors, effective clinical management for treating desmoid tumors has not been developed yet. Additionally, the molecular mechanisms involved in the tumorigenesis of desmoid tumors have not been elucidated. In this study, given the frequent mutations of Wnt components and loss of function mutations in Trp53 in desmoid tumors, we developed the mouse models harboring Apc mutation with/without Trp53 knockout, Apc1638N/+, and Apc1638N/+/Trp53-/-, respectively. We then established two primary cells derived from desmoid tumors in Apc1638N/+ and Apc1638N/+/Trp53-/-. Next, we have screened 3120 chemicals from a Food and Drug Administration-approved chemical library and identified halofuginone hydrobromide (HH), a collagen I-targeting compound, as exhibiting the most significant growth inhibition effects on Apc1638N/+ and Apc1638N/+/Trp53-/- desmoid tumor cells. Notably, HH also showed dramatic anticancer effects on colorectal cancer cells and mouse tumor organoids derived from intestinal tumors (Apc1638N/+). Taken together, targeting collagen I is an effective therapeutic strategy for treating desmoid tumors and colorectal cancer patients.