The Yin and Yang of Discoidin Domain Receptors (DDRs): Implications in Tumor Growth and Metastasis Development

Abstract

The tumor microenvironment is a complex structure composed of the extracellular matrix (ECM) and nontumoral cells (notably cancer-associated fibroblasts (CAFs) and immune cells). Collagens are the main components of the ECM and they are extensively remodeled during tumor progression. Some collagens are ligands for the discoidin domain receptor tyrosine kinases, DDR1 and DDR2. DDRs are involved in different stages of tumor development and metastasis formation. In this review, we present the different roles of DDRs in these processes and discuss controversial findings. We conclude by describing emerging DDR inhibitory strategies, which could be used as new alternatives for the treatment of patients.

The Journey of DDR1 and DDR2 Kinase Inhibitors as Rising Stars in the Fight Against Cancer

“…As a key component of the tumor extracellular matrix, type I collagen shows high density and distorted architecture in malignant cancer, linking it to tumor formation and metastasis [ 83 ]. Therefore, the discovery of DDRs as collagen receptors represents a new target in the regulation of tumor progression [ 84 , 85 , 86 , 87 , 88 , 89 ].…”

Collagen and Discoidin Domain Receptor 1 Partnership: A Multifaceted Role in the Regulation of Breast Carcinoma Cell Phenotype

“…A similar pro-apoptotic function of DDR1 was demonstrated in HT-29 colon carcinoma cells encapsulated in 3D COL1 (Le et al, 2020). These observations contrast with the classical concept that DDR1 expression in cancer cells is associated with an increased cell survival and proliferation (for review, see Majo and Auguste, 2021). Interestingly, a reduction in DDR1 mRNA levels was shown in most middle-to high-grade human breast carcinomas compared with normal mammary tissues (Neuhaus et al, 2011).…”

“…The same group has later shown that in an in-vivo mouse model of breast carcinoma, inhibition of DDR2 by the small-molecule allosteric inhibitor of DDR2 extracellular domain (WRG-28), was able to disrupt DDR2/COL1 interaction, thus leading to a decrease in SNAIL1 activity and an inhibition of DDR2 pro-metastatic effect ( Grither and Longmore, 2018 ). Interestingly, in those papers, DDR2 signaling was induced during EMT, but was not necessary for the induction of EMT ( Zhang et al, 2013 ; Majo and Auguste, 2021 ). Together, these data suggest a switch of DDRs expression during EMT.…”

“…More and more articles report the involvement of DDR1 and/or DDR2 in cancer and tumor invasion ( Leitinger, 2014 ; Henriet et al, 2018 ; Majo and Auguste, 2021 ). This trend has been confirmed for several years and reinforces the idea that these receptors are interesting as molecular targets to limit tumor progression.…”

Recent Advances in the Role of Discoidin Domain Receptor Tyrosine Kinase 1 and Discoidin Domain Receptor Tyrosine Kinase 2 in Breast and Ovarian Cancer

“…Dysregulation of DDR1 and DDR2 has been observed in many solid tumor types (including breast, ovarian, liver, gastric, colorectal, lung, brain, cervical, hematological, head and neck, melanoma, bladder, kidney, and prostate), and can be associated with aggressive metastatic tumors (including breast and ovarian) and a poor prognosis (Gadiya and Chakraborty, 2018; Orgel and Madhurapantula (2019). Yeh et al, 2019;Lafitte et al, 2020;Majo and Auguste, 2021). As discussed above, DDR dysregulation leads to many alterations which influence tumor development, pathology, and key clinical characteristics (key altered clinicopathological features being treatment response and prognosis) (Borza and Pozzi, 2014;Mehta et al, 2021).…”