Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies

Gao, Yuan; Zhou, Jiuli; Li, Jin

doi:10.1111/cas.14789

Cited by 41 publications

(31 citation statements)

References 68 publications

(155 reference statements)

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“…Moreover, we demonstrated that DDR1 promotes thyroid cancer cell dedifferentiation and the acquisition of a stemlike phenotype by enhancing the IGF-2/IR-A autocrine signaling loop [9,10] and plays a critical role in promoting bladder cancer cell motility by linking the IGF1R and IR-A to the regulation of F-actin cytoskeleton dynamics [15]. Collectively, these data uncover novel, non-canonical DDR1 functions, which strongly support the pro-tumorigenic and pro-metastatic role of DDR1 [16][17][18].…”

Section: Introductionsupporting

confidence: 60%

DDR1 Affects Metabolic Reprogramming in Breast Cancer Cells by Cross-Talking to the Insulin/IGF System

et al. 2021

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The insulin receptor isoform A (IR-A), a dual receptor for insulin and IGF2, plays a role in breast cancer (BC) progression and metabolic reprogramming. Notably, discoidin domain receptor 1 (DDR1), a collagen receptor often dysregulated in cancer, is involved in a functional crosstalk and feed forward loop with both the IR-A and the insulin like growth factor receptor 1 (IGF1R). Here, we aimed at investigating whether DDR1 might affect BC cell metabolism by modulating the IGF1R and/or the IR. To this aim, we generated MCF7 BC cells engineered to stably overexpress either IGF2 (MCF7/IGF2) or the IR-A (MCF7/IR-A). In both cell models, we observed that DDR1 silencing induced a significant decrease of total ATP production, particularly affecting the rate of mitochondrial ATP production. We also observed the downregulation of key molecules implicated in both glycolysis and oxidative phosphorylation. These metabolic changes were not modulated by DDR1 binding to collagen and occurred in part in the absence of IR/IGF1R phosphorylation. DDR1 silencing was ineffective in MCF7 knocked out for DDR1. Taken together, these results indicate that DDR1, acting in part independently of IR / IGF1R stimulation, might work as a novel regulator of BC metabolism and should be considered as putative target for therapy in BC.

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Section: Introductionsupporting

confidence: 60%

DDR1 Affects Metabolic Reprogramming in Breast Cancer Cells by Cross-Talking to the Insulin/IGF System

et al. 2021

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“…DDR1 and DDR2 function as ECM signal transducers, binding to the ECM collagen, and initiating intra-cellular signaling ( Henriet et al, 2018 ). DDRs and their signaling pathways are promising targets for the development of new clinical treatments, particularly in cancers with altered DDR expression or function ( Gao et al, 2021 ).…”

Section: Discoidin Domain Receptor Tyrosine Kinasesmentioning

confidence: 99%

“…Interestingly, many DDR signaling pathways (including IGF-DDR) can be used to treat chronic inflammatory diseases, including cancer ( Vella et al, 2019 ). While we have focused here on DDR1 and DDR2 in breast and ovarian cancer, they are increasingly important and relevant anti-cancer targets for multiple tumor types ( Lafitte et al, 2020 ; Bhanumathy et al, 2021 ; Gao et al, 2021 ). Previously Merestinib (LY2801653; inhibiting DDR1/2 and MET, MST1R, FLT3, AXL, MERTK, TEK, ROS1, and MKNK1/2) has shown potent anti-tumor activity in clinical trials against multiple advanced cancers ( Yan et al, 2013 ).…”

Section: Clinical Developments Of Discoidin Domain Receptor Tyrosine Kinase 1 and Discoidin Domain Receptor Tyrosine Kinase 2 Targeted Thmentioning

confidence: 99%

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

Chen

Kong

Fang

et al. 2021

Front. Cell Dev. Biol.

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Discoidin domain receptor tyrosine kinases (DDRs) are a class of receptor tyrosine kinases (RTKs), and their dysregulation is associated with multiple diseases (including cancer, chronic inflammatory conditions, and fibrosis). The DDR family members (DDR1a-e and DDR2) are widely expressed, with predominant expression of DDR1 in epithelial cells and DDR2 in mesenchymal cells. Structurally, DDRs consist of three regions (an extracellular ligand binding domain, a transmembrane domain, and an intracellular region containing a kinase domain), with their kinase activity induced by receptor-specific ligand binding. Collagen binding to DDRs stimulates DDR phosphorylation activating kinase activity, signaling to MAPK, integrin, TGF-β, insulin receptor, and Notch signaling pathways. Abnormal DDR expression is detected in a range of solid tumors (including breast, ovarian, cervical liver, gastric, colorectal, lung, and brain). During tumorigenesis, abnormal activation of DDRs leads to invasion and metastasis, via dysregulation of cell adhesion, migration, proliferation, secretion of cytokines, and extracellular matrix remodeling. Differential expression or mutation of DDRs correlates with pathological classification, clinical characteristics, treatment response, and prognosis. Here, we discuss the discovery, structural characteristics, organizational distribution, and DDR-dependent signaling. Importantly, we highlight the key role of DDRs in the development and progression of breast and ovarian cancer.

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“…DDR are activated by binding to the collagen and can activate signal transduction pathways. At the same time, DDR can regulate cell-collagen interactions which involved in multiple processes such as cell proliferation, migration, and apoptosis ( Gao et al, 2021 ). Moreover, the IIGFs-DDR1 crosstalk is considered the major mediator of therapy resistance of cancer cells ( Buck et al, 2010 ; Vella et al, 2019 ).…”

Section: Microenvironment and Cam-drmentioning

confidence: 99%

CAM-DR: Mechanisms, Roles and Clinical Application in Tumors

Huang

Wang

Tang

et al. 2021

Front. Cell Dev. Biol.

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Despite the continuous improvement of various therapeutic techniques, the overall prognosis of tumors has been significantly improved, but malignant tumors in the middle and advanced stages still cannot be completely cured. It is now evident that cell adhesion-mediated resistance (CAM-DR) limits the success of cancer therapies and is a great obstacle to overcome in the clinic. The interactions between tumor cells and extracellular matrix (ECM) molecules or adjacent cells may play a significant role in initiating the intracellular signaling pathways that are associated with cell proliferation, survival upon binding to their ligands. Recent studies illustrate that these adhesion-related factors may contribute to the survival of cancer cells after chemotherapeutic therapy, advantageous to resistant cells to proliferate and develop multiple mechanisms of drug resistance. In this review, we focus on the molecular basis of these interactions and the main signal transduction pathways that are involved in the enhancement of the cancer cells’ survival. Furthermore, therapies targeting interactions between cancer cells and their environment to enhance drug response or prevent the emergence of drug resistance will also be discussed.

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Discoidin domain receptors orchestrate cancer progression: A focus on cancer therapies

Cited by 41 publications

References 68 publications

DDR1 Affects Metabolic Reprogramming in Breast Cancer Cells by Cross-Talking to the Insulin/IGF System

DDR1 Affects Metabolic Reprogramming in Breast Cancer Cells by Cross-Talking to the Insulin/IGF System

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

CAM-DR: Mechanisms, Roles and Clinical Application in Tumors

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