Codon Bias of the DDR1 Gene and Transcription Factor EHF in Multiple Species.

Milk production is an essential economic trait in cattle, and understanding the genetic regulation of this trait can enhance breeding strategies. The discoidin domain receptor 1 (DDR1) gene has been identified as a key candidate gene that influences milk production, and ETS homologous factor (EHF) is recognized as a critical transcription factor that regulates DDR1 expression. Codon usage bias, which affects gene expression and protein function, has not been fully explored in cattle. This study aims to examine the codon usage bias of DDR1 and EHF transcription factors to understand their roles in dairy production traits. Data from 24 species revealed that both DDR1 and EHF predominantly used G/C-ending codons, with the GC3 content averaging 75.49% for DDR1 and 61.72% for EHF. Synonymous codon usage analysis identified high-frequency codons for both DDR1 and EHF, with 17 codons common to both genes. Correlation analysis indicated a negative relationship between the effective number of codons and codon adaptation index for both DDR1 and EHF. Phylogenetic and clustering analyses revealed similar codon usage patterns among closely related species. These findings suggest that EHF plays a crucial role in regulating DDR1 expression, offering new insights into genetically regulating milk production in cattle.

DDR1 is a Novel Biomarker and Potential Therapeutic Target for the Combination Treatment of Liver Hepatocellular Carcinoma.

AIM: This study aimed to investigate the role of discoidin domain receptor tyrosine kinase 1 (DDR1) in liver hepatocellular carcinoma (LIHC) and to evaluate its prognostic value on patient response to combination therapy. METHODS: In the current retrospective study, we examined the protein expression of DDR1 in various cancers by standard immunohistochemical (IHC) methods and evaluated its clinical significance in LIHC personalized treatment. Multiple online databases, including The Cancer Genome Atlas (TCGA), TIMER, GEO, ROC Plotter, and Genomics of Drug Sensitivity in Cancer (GDSC), were used. RESULTS: DDR1 protein expression was higher in LIHC than in other nine examined cancer types. Additionally, DDR1 exhibited higher expression levels in adjacent normal tissues compared to HBs-positive LIHC tissues. Analysis at single-cell resolution revealed that DDR1 was expressed primarily in epithelial cells but not in stromal and immune cells, and DDR1 expression was lower in HBs-positive LIHC cells in comparison with normal hepatocytes. Correlation of DDR1 upregulation and sorafenib resistance was observed in the patient cohort. Moreover, DDR1 expression positively correlated with the expression of inflammatory response-related genes, ECM-related genes, and collagen formation-related genes, but negatively correlated with the infiltration of CD8+ T cells, NK cells, and dendritic cells in LIHC. CONCLUSIONS: Our findings suggest that DDR1 expression might be induced by collagen production-related cellular events involved in liver injury and repair, and that DDR1 overexpression might contribute to the resistance to LIHC targeted therapy and immunotherapy, highlighting DDR1 as a potential prognostic biomarker and therapeutic target.

This study aimed to investigate the role of discoidin domain receptor tyrosine kinase 1 (DDR1) in liver hepatocellular carcinoma (LIHC) and to evaluate its prognostic value on patient response to combination therapy. In the current retrospective study, we examined the protein expression of DDR1 in various cancers by standard immunohistochemical (IHC) methods and evaluated its clinical significance in LIHC personalized treatment. Multiple online databases, including The Cancer Genome Atlas (TCGA), TIMER, GEO, ROC Plotter, and Genomics of Drug Sensitivity in Cancer (GDSC), were used. DDR1 protein expression was higher in LIHC than in other nine examined cancer types. Additionally, DDR1 exhibited higher expression levels in adjacent normal tissues compared to HBs-positive LIHC tissues. Analysis at single-cell resolution revealed that DDR1 was expressed primarily in epithelial cells but not stromal cells and immune cells, and DDR1 expression was lower in HBs-positive LIHC cells in comparison with normal hepatocytes. Correlation of DDR1 upregulation and sorafenib resistance was observed in patient cohort. Moreover, DDR1 expression positively correlated with the expression of inflammatory response-related genes, ECM-related genes, and collagen formation-related genes but negatively correlated with the infiltration of CD8 + T cells, NK cells, and dendritic cells in LIHC. Our findings suggest that DDR1 expression might be induced by collagen production-related cellular events involved in liver injury and repair and that DDR1 overexpression might contribute to the resistance to LIHC targeted therapy and immunotherapy, highlighting DDR1 as a potential prognostic biomarker and therapeutic target.

Inhibition of DDR1 promotes ferroptosis and overcomes gefitinib resistance in non-small cell lung cancer.

Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), which serves the critical pillar for the treatment of non-small cell lung cancer (NSCLC). However, the acquired resistance remains a challenge for its clinical application, for which, practical strategies to reverse gefitinib resistance in NSCLC are necessary. Ferroptosis, a programmed cell death driven by ferritin-dependent lipid peroxidation, involves in NSCLC progression and related chemoresistance. In our previous work, the self-synthesised EGFR inhibitor Yfq07 (N4, N6-disubstituted pyrimidine-4,6-diamine derivatives) displayed a considerable inhibitory effect on NSCLC both in vitro and in vivo. Herein, we observed that Yfq07 suppressed the proliferation of PC-9GR and HCC827GR cells, two gefitinib resistance NSCLC cell lines. Mechanically, Yfq07 inhibited the phosphorylation of the Discoidin Domain Receptor 1 (DDR1), a receptor tyrosine kinase (RTK) highly expressed in multiple cancers, accompanied by downregulated miR-3648 and upregulated SOCS2. Inhibition or knockdown of DDR1 suppressed the proliferation, migration, and invasion of gefitinib-resistant NSCLC cells, and on the other hand, also downregulated miR-3648 and promoted SOCS2 expression. More specifically, miR-3648 targeted the 3'UTR segment of SOCS2 mRNA and thus affecting the P-ERK signalling pathway to regulate the malignant behaviors of gefitinib-resistant NSCLC cells. Furthermore, Yfq07 also indirectly induced the ferroptosis of gefitinib-resistant NSCLC cells via SOCS2 triggered inhibition of xCT-GPX4 pathway. In conclusion, our study indicates that DDR1 inhibitor Yfq07 promotes ferroptosis and reverses gefitinib-resistance of NSCLC through DDR1-miR-3648-SOCS2 signalling pathway, which provides insights for targeted therapy of gefitinib-resistant NSCLC and drug developments targeting ferroptosis.

Functional Role of DDR1 in Oligodendrocyte Signaling Mechanism in Association with Myelination and Remyelination Process in the Central Nerve System.

ABSTRACT: Multiple sclerosis (MS) is a complicated, inflammatory disease that causes demyelination of the central nervous system (CNS), resulting in a variety of neurological abnormalities. Over the past several decades, different animal models have been used to replicate the clinical symptoms and neuropathology of MS. The experimental model of experimental autoimmune/allergic encephalomyelitis (EAE) and viral and toxin-induced model was widely used to investigate the clinical implications of MS. Discoidin domain receptor 1 (DDR1) signaling in oligodendrocytes (OL) brings a new dimension to our understanding of MS pathophysiology. DDR1 is effectively involved in the OL during neurodevelopment and remyelination. It has been linked to many cellular processes, including migration, invasion, proliferation, differentiation, and adhesion. However, the exact functional involvement of DDR1 in developing OL and myelinogenesis in the CNS remains undefined. In this review, we critically evaluate the current literature on DDR1 signaling in OL and its proliferation, migration, differentiation, and myelination mechanism in OL in association with the progression of MS. It increases our knowledge of DDR1 in OL as a novel target molecule for oligodendrocyte-associated diseases in the CNS, including MS.

A highly selective inhibitor of discoidin domain receptor-1 (DDR1-IN-1) protects corneal epithelial cells from YAP/ACSL4-mediated ferroptosis in dry eye.

BACKGROUND AND PURPOSE: This study investigated the involvement of discoidin domain receptor (DDR) in dry eye and assessed the potential of specific DDR inhibitors as a therapeutic strategy for dry eye by exploring the underlying mechanism. EXPERIMENTAL APPROACH: Dry eye was induced in Wistar rats by applying 0.2% benzalkonium chloride (BAC), after which rats were treated topically for 7 days with DDR1-IN-1, a selective inhibitor of DDR1. Clinical manifestations of dry eye were assessed on Day-7 post-treatment. Histological evaluation of corneal damage was performed using haematoxylin and eosin (H&E) staining. In vitro, immortalized human corneal epithelial cells (HCECs) exposed to hyperosmotic stress (HS) were treated with varying doses of DDR1-IN-1 for 24 h. The levels of lipid peroxidation in dry eye corneas or HS-stimulated HCECs were assessed. Protein levels of DDR1/DDR2 and related pathways were detected by western blotting. The cellular distribution of acyl-CoA synthetase long chain family member 4 (ACSL4) and Yes-associated protein (YAP) was evaluated using immunohistochemistry or immunofluorescent staining. KEY RESULTS: In dry eye corneas, only DDR1 expression was significantly up-regulated compared with normal controls. DDR1-IN-1 treatment significantly alleviated dry eye symptoms in vivo. The treatment remarkably reduced lipid hydroperoxide (LPO) levels and suppressed the expression of ferroptosis markers, particularly ACSL4. Overexpression or reactivation of YAP diminished the protective effects of DDR1-IN-1, indicating the involvement of the Hippo/YAP pathway in DDR1-targeted therapeutic effects. CONCLUSIONS AND IMPLICATIONS: This study confirms the significance of DDR1 in dry eye and highlights the potential of selective DDR1 inhibitor(s) for dry eye treatment.

Overcoming the Tumor Collagen Barriers: A Multistage Drug Delivery Strategy for DDR1-Mediated Resistant Colorectal Cancer Therapy.

The extracellular matrix (ECM) is critical for drug resistance in colorectal cancer (CRC). The abundant collagen within the ECM significantly influences tumor progression and matrix-mediated drug resistance (MMDR) by binding to discoidin domain receptor 1 (DDR1), but the specific mechanisms by which tumor cells modulate ECM via DDR1 and ultimately regulate TME remain poorly understand. Furthermore, overcoming drug resistance by modulating the tumor ECM remains a challenge in CRC treatment. In this study, a novel mechanism is elucidated by which DDR1 mediates the interactions between tumor cells and collagen, enhances collagen barriers, inhibits immune infiltration, promotes drug efflux, and leads to MMDR in CRC. To address this issue, a multistage drug delivery system carrying DDR1-siRNA and chemotherapeutic agents is employed to disrupt collagen barriers by silencing DDR1 in tumor, enhancing chemotherapy drugs diffusion and facilitating immune infiltration. These findings not only revealed a novel role for collagen-rich matrix mediated by DDR1 in tumor resistance, but also introduced a promising CRC treatment strategy.

DDR1 Drives Malignant Progression of Gastric Cancer by Suppressing HIF-1α Ubiquitination and Degradation.

The extracellular matrix (ECM) has been demonstrated to be dysregulated and crucial for malignant progression in gastric cancer (GC), but the mechanism is not well understood. Here, that discoidin domain receptor 1 (DDR1), a principal ECM receptor, is recognized as a key driver of GC progression is reported. Mechanistically, DDR1 directly interacts with the PAS domain of hypoxia-inducible factor-1α (HIF-1α), suppresses its ubiquitination and subsequently strengthens its transcriptional regulation of angiogenesis. Additionally, DDR1 upregulation in GC cells promotes actin cytoskeleton reorganization by activating HIF-1α/ Ras Homolog Family Member A (RhoA)/Rho-associated protein kinase 1 (ROCK1) signaling, which in turn enhances the metastatic capacity. Pharmacological inhibition of DDR1 suppresses GC progression and angiogenesis in patient-derived xenograft (PDX) and organoid models. Taken together, this work first indicates the effects of the DDR1-HIF-1α axis on GC progression and reveals the related mechanisms, providing experimental evidence for DDR1 as a therapeutic target for GC.

Discovery of a prominent dual-target DDR1/EGFR inhibitor aimed DDR1/EGFR-positive NSCLC.

This study aimed to develop the first dual-target small molecule inhibitor concurrently targeting Discoidin domain receptor 1 (DDR1) and Epidermal growth factor receptor (EGFR), which play a crucial interdependent roles in non-small cell lung cancer (NSCLC), demonstrating a synergistic inhibitory effect. A series of innovative dual-target inhibitors for DDR1 and EGFR were discovered. These compounds were designed and synthesized using structural optimization strategies based on the lead compound BZF02, employing 4,6-pyrimidine diamine as the core scaffold, followed by an investigation of their biological activities. Among these compounds, D06 was selected and showed micromolar enzymatic potencies against DDR1 and EGFR. Subsequently, compound D06 was observed to inhibit NSCLC cell proliferation and invasion. Demonstrating acceptable pharmacokinetic performance, compound D06 exhibited its anti-tumor activity in NSCLC PC-9/GR xenograft models without apparent toxicity or significant weight loss. These collective results showcase the successful synthesis of a potent dual-targeted inhibitor, suggesting the potential therapeutic efficacy of co-targeting DDR1 and EGFR for DDR1/EGFR-positive NSCLC.

Discovery of LLC355 as an Autophagy-Tethering Compound for the Degradation of Discoidin Domain Receptor 1.

Discoidin domain receptor 1 (DDR1) is a potential target for cancer drug discovery. Although several DDR1 kinase inhibitors have been developed, recent studies have revealed the critical roles of the noncatalytic functions of DDR1 in tumor progression, metastasis, and immune exclusion. Degradation of DDR1 presents an opportunity to block its noncatalytic functions. Here, we report the discovery of the DDR1 degrader LLC355 by employing autophagosome-tethering compound technology. Compound LLC355 efficiently degraded DDR1 protein with a DC50 value of 150.8 nM in non-small cell lung cancer NCI-H23 cells. Mechanistic studies revealed compound LLC355 to induce DDR1 degradation via lysosome-mediated autophagy. Importantly, compound LLC355 potently suppressed cancer cell tumorigenicity, migration, and invasion and significantly outperformed the corresponding inhibitor 1. These results underline the therapeutic advantage of targeting the noncatalytic function of DDR1 over inhibition of its kinase activity.

Inactivation of kindlin-3 increases human melanoma aggressiveness through the collagen-activated tyrosine kinase receptor DDR1.

The role of the focal adhesion protein kindlin-3 as a tumor suppressor and its interaction mechanisms with extracellular matrix constitute a major field of investigation to better decipher tumor progression. Besides the well-described role of kindlin-3 in integrin activation, evidence regarding modulatory functions between melanoma cells and tumor microenvironment are lacking and data are needed to understand mechanisms driven by kindlin-3 inactivation. Here, we show that kindlin-3 inactivation through knockdown or somatic mutations increases BRAFV600mut melanoma cells oncogenic properties via collagen-related signaling by decreasing cell adhesion and enhancing proliferation and migration in vitro, and by promoting tumor growth in mice. Mechanistic analysis reveals that kindlin-3 interacts with the collagen-activated tyrosine kinase receptor DDR1 (Discoidin domain receptor 1) modulating its expression and its interaction with ß1-integrin. Kindlin-3 knockdown or mutational inactivation disrupt DDR1/ß1-integrin complex in vitro and in vivo and its loss improves the anti-proliferative effect of DDR1 inhibition. In agreement, kindlin-3 downregulation is associated with DDR1 over-expression in situ and linked to worse melanoma prognosis. Our study reveals a unique mechanism of action of kindlin-3 in the regulation of tumorigenesis mediated by the collagen-activated tyrosine kinase receptor DDR1 thus paving the way for innovative therapeutic targeting approaches in melanoma.

DDR1-targeted therapies: current limitations and future potential.

Discoidin domain receptor (DDR)-1 has a crucial role in regulating vital processes, including cell differentiation, proliferation, adhesion, migration, invasion, and matrix remodeling. Overexpression or activation of DDR1 in various pathological scenarios makes it a potential therapeutic target for the treatment of cancer, fibrosis, atherosclerosis, and neuropsychiatric, psychiatric, and neurodegenerative disorders. In this review, we summarize current therapeutic approaches targeting DDR1 from a medicinal chemistry perspective. Furthermore, we analyze factors other than issues of low selectivity and risk of resistance, contributing to the infrequent success of DDR1 inhibitors. The complex interplay between DDR1 and the extracellular matrix (ECM) necessitates additional validation, given that DDR1 might exhibit complex and synergistic interactions with other signaling molecules during ECM regulation. The mechanisms involved in DDR1 regulation in cancer and inflammation-related diseases also remain unknown.

Associations of altered leukocyte DDR1 promoter methylation and childhood trauma with bipolar disorder and suicidal behavior in euthymic patients.

Altered DNA methylation (DNAm) patterns of discoidin domain receptor 1 (DDR1) have been found in the blood and brain of patients with schizophrenia (SCZ) and the brain of patients with bipolar disorder (BD). Childhood trauma (CT) is associated with changes in DNAm that in turn are related to suicidal behavior (SB) in patients with several psychiatric disorders. Here, using MassARRAY® technology, we studied 128 patients diagnosed with BD in remission and 141 healthy controls (HCs) to compare leukocyte DDR1 promoter DNAm patterns between patients and HCs and between patients with and without SB. Additionally, we investigated whether CT was associated with DDR1 DNAm and mediated SB. We found hypermethylation at DDR1 cg19215110 and cg23953820 sites and hypomethylation at cg14279856 and cg03270204 sites in patients with BD compared to HCs. Logistic regression models showed that hypermethylation of DDR1 cg23953820 but not cg19215110 and CT were risk factors for BD, while cg14279856 and cg03270204 hypomethylation were protective factors. In patients, CT was a risk factor for SB, but DDR1 DNAm, although associated with CT, did not mediate the association of CT with SB. This is the first study demonstrating altered leukocyte DDR1 promoter DNAm in euthymic patients with BD. We conclude that altered DDR1 DNAm may be related to immune and inflammatory mechanisms and could be a potential blood biomarker for the diagnosis and stratification of psychiatric patients.

Coexpression network analysis of the adult brain sheds light on the pathogenic mechanism of DDR1 in schizophrenia and bipolar disorder.

DDR1 has been linked to schizophrenia (SCZ) and bipolar disorder (BD) in association studies. DDR1 encodes 58 distinct transcripts, which can be translated into five isoforms (DDR1a-e) and are expressed in the brain. However, the transcripts expressed in each brain cell type, their functions and their involvement in SCZ and BD remain unknown. Here, to infer the processes in which DDR1 transcripts are involved, we used transcriptomic data from the human brain dorsolateral prefrontal cortex of healthy controls (N = 936) and performed weighted gene coexpression network analysis followed by enrichment analyses. Then, to explore the involvement of DDR1 transcripts in SCZ (N = 563) and BD (N = 222), we studied the association of coexpression modules with disease and performed differential expression and transcript significance analyses. Some DDR1 transcripts were distributed across five coexpression modules identified in healthy controls (MHC). MHC1 and MHC2 were enriched in the cell cycle and proliferation of astrocytes and OPCs; MHC3 and MHC4 were enriched in oligodendrocyte differentiation and myelination; and MHC5 was enriched in neurons and synaptic transmission. Most of the DDR1 transcripts associated with SCZ and BD pertained to MHC1 and MHC2. Altogether, our results suggest that DDR1 expression might be altered in SCZ and BD via the proliferation of astrocytes and OPCs, suggesting that these processes are relevant in psychiatric disorders.

Processing speed mediates the relationship between DDR1 and psychosocial functioning in euthymic patients with bipolar disorder presenting psychotic symptoms.

The DDR1 locus is associated with the diagnosis of schizophrenia and with processing speed in patients with schizophrenia and first-episode psychosis. Here, we investigated whether DDR1 variants are associated with bipolar disorder (BD) features. First, we performed a case‒control association study comparing DDR1 variants between patients with BD and healthy controls. Second, we performed linear regression analyses to assess the associations of DDR1 variants with neurocognitive domains and psychosocial functioning. Third, we conducted a mediation analysis to explore whether neurocognitive impairment mediated the association between DDR1 variants and psychosocial functioning in patients with BD. Finally, we studied the association between DDR1 variants and white matter microstructure. We did not find any statistically significant associations in the case‒control association study; however, we found that the combined genotypes rs1264323AA-rs2267641AC/CC were associated with worse neurocognitive performance in patients with BD with psychotic symptoms. In addition, the combined genotypes rs1264323AA-rs2267641AC/CC were associated with worse psychosocial functioning through processing speed. We did not find correlations between white matter microstructure abnormalities and the neurocognitive domains associated with the combined genotypes rs1264323AA-rs2267641AC/CC. Overall, the results suggest that DDR1 may be a marker of worse neurocognitive performance and psychosocial functioning in patients with BD, specifically those with psychotic symptoms.

Novel insights into the role of Discoidin domain receptor 2 (DDR2) in cancer progression: a new avenue of therapeutic intervention.

Discoidin domain receptors (DDRs), including DDR1 and DDR2, are a unique class of receptor tyrosine kinases (RTKs) activated by collagens at the cell-matrix boundary interface. The peculiar mode of activation makes DDRs as key cellular sensors of microenvironmental changes, with a critical role in all physiological and pathological processes governed by collagen remodeling. DDRs are widely expressed in fetal and adult tissues, and experimental and clinical evidence has shown that their expression is deregulated in cancer. Strong findings supporting the role of collagens in tumor progression and metastasis have led to renewed interest in DDRs.  However, despite an increasing number of studies, DDR biology remains poorly understood, particularly the less studied DDR2, whose involvement in cancer progression mechanisms is undoubted. Thus, the understanding of a wider range of DDR2 functions and related molecular mechanisms is expected. To date, several lines of evidence support DDR2 as a promising target in cancer therapy. Its involvement in key functions in the tumor microenvironment makes DDR2 inhibition particularly attractive to achieve simultaneous targeting of tumor and stromal cells, and tumor regression, which is beneficial for improving the response to different types of anti-cancer therapies, including chemo- and immunotherapy. This review summarizes current research on DDR2, focusing on its role in cancer progression through its involvement in tumor and stromal cell functions, and discusses findings that support the rationale for future development of direct clinical strategies targeting DDR2.

Blockade of DDR1/PYK2/ERK signaling suggesting SH2 superbinder as a novel autophagy inhibitor for pancreatic cancer.

Pancreatic cancer is highly lethal, of which 90% is pancreatic ductal adenocarcinoma (PDAC), with a 5-year survival rate of less than 12%, lacking effective treatment options and late diagnosis. Furthermore, the tumors show an intense resistance to cytotoxic chemotherapies. As autophagy is elevated in PDAC, targeting the autophagic pathway is regarded as a promising strategy for cancer treatment. Immunofluorescence and transmission electron microscopy were utilized to assess the autophagic flux. Label-free quantitative phosphoproteomics was used to figure out critically altered tyrosine phosphorylation of the proteins. Tumor-bearing mice were used to validate that SH2 TrM-(Arg)9 restrained the growth of tumor cells. SH2 TrM-(Arg)9 inhibited collagen-induced autophagy via blocking the DDR1/PYK2/ERK signaling cascades. SH2 TrM-(Arg)9 improved the sensitivity of PANC-1/GEM cells to gemcitabine (GEM). Inhibition of autophagy by SH2 TrM-(Arg)9 may synergized with chemotherapy and robusted tumor suppression in pancreatic cancer xenografts. SH2 TrM-(Arg)9 could enter into PDAC cells and blockade autophagy through inhibiting DDR1/PYK2/ERK signaling and may be a new treatment strategy for targeted therapy of PDAC.

Endothelial discoidin domain receptor 1 senses flow to modulate YAP activation.

Mechanotransduction in endothelial cells is critical to maintain vascular homeostasis and can contribute to disease development, yet the molecules responsible for sensing flow remain largely unknown. Here, we demonstrate that the discoidin domain receptor 1 (DDR1) tyrosine kinase is a direct mechanosensor and is essential for connecting the force imposed by shear to the endothelial responses. We identify the flow-induced activation of endothelial DDR1 to be atherogenic. Shear force likely causes conformational changes of DDR1 ectodomain by unfolding its DS-like domain to expose the buried cysteine-287, whose exposure facilitates force-induced receptor oligomerization and phase separation. Upon shearing, DDR1 forms liquid-like biomolecular condensates and co-condenses with YWHAE, leading to nuclear translocation of YAP. Our findings establish a previously uncharacterized role of DDR1 in directly sensing flow, propose a conceptual framework for understanding upstream regulation of the YAP signaling, and offer a mechanism by which endothelial activation of DDR1 promotes atherosclerosis.

Exploring the Cellular and Molecular Mechanism of Discoidin Domain Receptors (DDR1 and DDR2) in Bone Formation, Regeneration, and Its Associated Disease Conditions.

The tyrosine kinase family receptor of discoidin domain receptors (DDR1 and DDR2) is known to be activated by extracellular matrix collagen catalytic binding protein receptors. They play a remarkable role in cell proliferation, differentiation, migration, and cell survival. DDR1 of the DDR family regulates matrix-metalloproteinase, which causes extracellular matrix (ECM) remodeling and reconstruction during unbalanced homeostasis. Collagenous-rich DDR1 triggers the ECM of cartilage to regenerate the cartilage tissue in osteoarthritis (OA) and temporomandibular disorder (TMD). Moreover, DDR2 is prominently present in the fibroblasts, smooth muscle cells, myofibroblasts, and chondrocytes. It is crucial in generating and breaking collagen vital cellular activities like proliferation, differentiation, and adhesion mechanisms. However, the deficiency of DDR1 rather than DDR2 was detrimental in cases of OA and TMDs. DDR1 stimulated the ECM cartilage and improved bone regeneration. Based on the above information, we made an effort to outline the advancement of the utmost promising DDR1 and DDR2 regulation in bone and cartilage, also summarizing their structural, biological activity, and selectivity.

Discoidin Domain Receptor Tyrosine Kinase 1 (DDR1) Is a Novel Therapeutic Target in Liposarcoma: A Tissue Microarray Study.

BACKGROUND: Liposarcoma is the most commonly diagnosed subtype of soft tissue sarcoma. As these tumors often arise near vital organs and neurovascular structures, complete resection can be challenging; consequently, recurrence rates are high. Additionally, available chemotherapeutic agents have shown limited benefit and substantial toxicities. There is, therefore, a clear and unmet need for novel therapeutics for liposarcoma. Discoidin domain receptor tyrosine kinase 1 (DDR1) is involved in adhesion, proliferation, differentiation, migration, and metastasis in several cancers. However, the expression and clinical importance of DDR1 in liposarcoma are unknown. QUESTIONS/PURPOSES: The purposes of this study were to assess (1) the expression, (2) the association between DDR1 and survival, and (3) the functional roles of DDR1 in liposarcoma. METHODS: The correlation between DDR1 expression in tumor tissues and clinicopathological features and survival was assessed via immunohistochemical staining of a liposarcoma tissue microarray. It contained 53 samples from 42 patients with liposarcoma and 11 patients with lipoma. The association between DDR1 and survival in liposarcoma was analyzed by Kaplan-Meier plots and log-rank tests. The DDR1 knockout liposarcoma cell lines were generated by CRISPR-Cas9 technology. The DDR1-specific and highly selective DDR1 inhibitor 7RH was applied to determine the impact of DDR1 expression on liposarcoma cell growth and proliferation. In addition, the effect of DDR1 inhibition on liposarcoma growth was further accessed in a three-dimensional cell culture model to mimic DDR1 effects in vivo. RESULTS: The results demonstrate elevated expression of DDR1 in all liposarcoma subtypes relative to benign lipomas. Specifically, high DDR1 expression was seen in 55% (23 of 42) of liposarcomas and no benign lipomas. However, DDR1 expression was not found to be associated with poor survival in patients with liposarcoma. DDR1 knockout or treatment of 7RH showed decreased liposarcoma cell growth and proliferation. CONCLUSION: DDR1 is aberrantly expressed in liposarcoma, and it contributes to several markers of oncogenesis in these tumors. CLINICAL RELEVANCE: This work supports DDR1 as a promising therapeutic target in liposarcoma.

Evidence That DDR1 Promotes Oligodendrocyte Differentiation during Development and Myelin Repair after Injury.

Oligodendrocytes generate myelin sheaths vital for the formation, health, and function of the central nervous system. Mounting evidence suggests that receptor tyrosine kinases (RTKs) are crucial for oligodendrocyte differentiation and myelination in the CNS. It was recently reported that discoidin domain receptor 1 (Ddr1), a collagen-activated RTK, is expressed in oligodendrocyte lineage. However, its specific expression stage and functional role in oligodendrocyte development in the CNS remain to be determined. In this study, we report that Ddr1 is selectively upregulated in newly differentiated oligodendrocytes in the early postnatal CNS and regulates oligodendrocyte differentiation and myelination. Ddr1 knock-out mice of both sexes displayed compromised axonal myelination and apparent motor dysfunction. Ddr1 deficiency alerted the ERK pathway, but not the AKT pathway in the CNS. In addition, Ddr1 function is important for myelin repair after lysolecithin-induced demyelination. Taken together, the current study described, for the first time, the role of Ddr1 in myelin development and repair in the CNS, providing a novel molecule target for the treatment of demyelinating diseases.