Tyrosine kinase-independent actions of DDR2 in tumor cells and cancer-associated fibroblasts influence tumor invasion, migration and metastasis.

Craig E. Barcus,Gregory D. Longmore,Audrey Brenot,Patrick Pence,Vasilios Morikis,Priscilla Y. Hwang,Maria Clarke

doi:10.1242/jcs.258431

Abstract

ABSTRACTBoth tumor cell-intrinsic signals and tumor cell-extrinsic signals from cells within the tumor microenvironment influence tumor cell dissemination and metastasis. The fibrillar collagen receptor tyrosine kinase (RTK) discoidin domain receptor 2 (DDR2) is essential for breast cancer metastasis in mouse models, and high expression of DDR2 in tumor and tumor stromal cells is strongly associated with poorer clinical outcomes. DDR2 tyrosine kinase activity has been hypothesized to be required for the metastatic activity of DDR2; however, inhibition of DDR2 tyrosine kinase activity, along with that of other RTKs, has failed to provide clinically relevant responses in metastatic patients. Here, we show that tyrosine kinase activity-independent action of DDR2 in tumor cells can support Matrigel invasion and in vivo metastasis. Paracrine actions of DDR2 in tumor cells and cancer-associated fibroblasts (CAFs) also support tumor invasion, migration and lung colonization in vivo. These data suggest that tyrosine kinase-independent functions of DDR2 could explain failures of tyrosine kinase inhibitor treatment in metastatic breast cancer patients and highlight the need for alternative therapeutic strategies that inhibit both tyrosine kinase-dependent and -independent actions of RTKs in the treatment of breast cancer.This article has an associated First Person interview with the first author of the paper.

Highlights

In epithelial tumors, such as breast cancer, abnormal or dysregulated receptor tyrosine kinase (RTK) signaling is common
Production and characterization of cell lines To determine the importance of the intracellular tyrosine kinase activity and tyrosine kinase domain of discoidin domain receptor 2 (DDR2) in supporting breast tumor cell invasion, migration and metastasis, we depleted DDR2 using shRNA treatment in a set of human (BT549, Hs578 T and MDA-MB-231) and mouse (4T1) breast tumor cell lines
There can be increased extracellular matrix (ECM) deposition and remodeling that leads to changes in tumor stiffness or other physical properties, which are factors that are hypothesized to contribute to tyrosine kinase inhibitors (TKIs) failure (Senthebane et al, 2017; Wang et al, 2019)

Summary

Introduction

In epithelial tumors, such as breast cancer, abnormal or dysregulated receptor tyrosine kinase (RTK) signaling is common. Expression of the RTK family of epidermal growth factor receptors (EGFRs) can be a clinical marker, and treatments directly targeting the EGFR family. DDR2 action in CAFs can increase tumor cell invasiveness through paracrine regulation (Corsa et al, 2016) These data make DDR2 an attractive therapeutic target for the prevention or treatment of metastatic breast cancer

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Conclusion