DDR2-regulated arginase activity in ovarian cancer-associated fibroblasts promotes collagen production and tumor progression

Abstract

Ovarian cancer has poor survival outcomes particularly for advanced stage, metastatic disease. Metastasis is promoted by interactions of stromal cells, such as cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), with tumor cells. CAFs play a key role in tumor progression by remodeling the TME and extracellular matrix (ECM) to result in a more permissive environment for tumor progression. It has been shown that fibroblasts, in particular myofibroblasts, utilize metabolism to support ECM remodeling. However, the intricate mechanisms by which CAFs support collagen production and tumor progression are poorly understood. In this study, we show that the fibrillar collagen receptor, Discoidin Domain Receptor 2 (DDR2), promotes collagen production in human and mouse omental CAFs through arginase activity. CAFs with high DDR2 or arginase promote tumor colonization in the omentum. In addition, DDR2-depleted CAFs had decreased ornithine levels leading to decreased collagen production and polyamine levels compared to WT control CAFs. Tumor cell invasion was decreased in the presence CAF conditioned media (CM) depleted of DDR2 or arginase-1, and this invasion defect was rescued in the presence of CM from DDR2-depleted CAFs that constitutively overexpressed arginase-1. Similarly, the addition of exogenous polyamines to CM from DDR2-depleted CAFs led to increased tumor cell invasion. We detected SNAI1 protein at the promoter region of the arginase-1 gene, and DDR2-depleted CAFs had decreased levels of SNAI1 protein at the arginase-1 promoter region. Furthermore, high stromal arginase-1 expression correlated with poor survival in ovarian cancer patients. These findings highlight how DDR2 regulates collagen production by CAFs in the tumor microenvironment by controlling the transcription of arginase-1, and CAFs are a major source of arginase activity and L-arginine metabolites in ovarian cancer models.

Recent advances in understanding the immune microenvironment in ovarian cancer

“…DDR2-depleted CAFs exhibited reduced levels of SNAI1 protein in the arginase-1 promoter region. These findings illustrate how DDR2 regulates collagen production by modulating arginase-1 transcription, which is a crucial source of arginase activity and L-arginine metabolites in OC models ( 86 ). Studies indicate that CAFs can communicate with neighboring cells through exosomes, thereby participating in OC initiation and progression.…”

Polyamines: the pivotal amines in influencing the tumor microenvironment

“…High expression of Discoidin Domain Receptor 2 (DDR2) promotes collagen production in both human and mouse omental CAFs. This collagen production is linked to ovarian tumor progression and occurs through increased arginase activity and polyamine production [ 119 ]. In pancreatic cancers, arginase-expressing CAFs were found to be a predictor of poorer overall survival.…”