RESUMO
BACKGROUND AND OBJECTIVE: While numerous in silico tools exist for target-based drug discovery, the inconsistent integration of in vitro data with predictive models hinders research and development productivity. This is particularly apparent during the Hit-to-Lead stage, where unreliable in-silico tools often lead to suboptimal lead selection. Herein, we address this challenge by presenting a CADD-guided pipeline that successfully integrates rational drug design with in-silico hits to identify a promising DDR1 lead. METHODS: 2 × 1000 ns MD simulations along with their respective FEL and MMPBSA analyses were employed to guide the rational design and synthesis of 12 novel compounds which were evaluated for their DDR inhibition. RESULTS: The molecular dynamics investigation of the initial hit led to the identification of key structural features within the DDR1 binding pocket. The identified key features were used to guide the rational design and synthesis of twelve novel derivatives. SAR analysis, biological evaluation, molecular dynamics, and free energy calculations were carried out for the synthesized derivatives to understand their mechanism of action. Compound 4c exhibited the strongest inhibition and selectivity for DDR1, with an IC50 of 0.11 µM. CONCLUSIONS: The MD simulations led to the identification of a key hydrophobic groove in the DDR1 binding pocket. The integrated approach of SAR analysis with molecular dynamics led to the identification of compound 4c as a promising lead for further development of potent and selective DDR1 inhibitors. Moreover, this work establishes a protocol for translating in silico hits to real world bioactive druggable leads.
Assuntos
Receptor com Domínio Discoidina 1 , Desenho de Fármacos , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases , Receptor com Domínio Discoidina 1/antagonistas & inibidores , Humanos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/síntese química , Desenho Assistido por Computador , Sítios de Ligação , Relação Estrutura-Atividade , Simulação de Acoplamento MolecularRESUMO
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.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células , Receptor com Domínio Discoidina 1 , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Humanos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Receptor com Domínio Discoidina 1/antagonistas & inibidores , Receptor com Domínio Discoidina 1/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Relação Estrutura-Atividade , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Animais , Estrutura Molecular , Camundongos , Descoberta de Drogas , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Experimentais/metabolismo , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB CRESUMO
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.
Assuntos
Autofagia , Receptor com Domínio Discoidina 1 , Humanos , Receptor com Domínio Discoidina 1/metabolismo , Receptor com Domínio Discoidina 1/antagonistas & inibidores , Autofagia/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Animais , Descoberta de Drogas , Movimento Celular/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Relação Estrutura-Atividade , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Proliferação de Células/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismoRESUMO
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.
Assuntos
Proliferação de Células , Receptor com Domínio Discoidina 1 , Melanoma , Proteínas de Membrana , Proteínas de Neoplasias , Humanos , Receptor com Domínio Discoidina 1/genética , Receptor com Domínio Discoidina 1/metabolismo , Animais , Melanoma/patologia , Melanoma/genética , Melanoma/metabolismo , Camundongos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proliferação de Células/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Linhagem Celular Tumoral , Integrina beta1/metabolismo , Integrina beta1/genética , Movimento Celular/genética , Adesão Celular/genética , Colágeno/metabolismo , Transdução de Sinais/genética , Regulação Neoplásica da Expressão GênicaRESUMO
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.
Assuntos
Receptor com Domínio Discoidina 1 , Terapia de Alvo Molecular , Neoplasias , Humanos , Receptor com Domínio Discoidina 1/metabolismo , Receptor com Domínio Discoidina 1/antagonistas & inibidores , Animais , Neoplasias/tratamento farmacológico , Matriz Extracelular/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase (RTK) and plays pivotal roles in regulating cellular functions such as proliferation, differentiation, invasion, migration, and matrix remodeling. DDR1 is involved in the occurrence and progression of many human diseases, including cancer, fibrosis, and inflammation. Therefore, DDR1 represents a highly promising therapeutic target. Although no selective small-molecule inhibitors have reached clinical trials to date, many molecules have shown therapeutic effects in preclinical studies. For example, BK40143 has demonstrated significant promise in the therapy of neurodegenerative diseases. In this context, our perspective aims to provide an in-depth exploration of DDR1, encompassing its structure characteristics, biological functions, and disease relevance. Furthermore, we emphasize the importance of understanding the structure-activity relationship of DDR1 inhibitors and highlight the unique advantages of dual-target or multitarget inhibitors. We anticipate offering valuable insights into the development of more efficacious DDR1-targeted drugs.
Assuntos
Receptor com Domínio Discoidina 1 , Neoplasias , Humanos , Receptores Proteína Tirosina Quinases , Colágeno , Neoplasias/tratamento farmacológico , InflamaçãoRESUMO
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.
Assuntos
Transtorno Bipolar , Receptor com Domínio Discoidina 1 , Esquizofrenia , Adulto , Humanos , Transtorno Bipolar/genética , Transtorno Bipolar/metabolismo , Encéfalo/metabolismo , Receptor com Domínio Discoidina 1/genética , Receptor com Domínio Discoidina 1/metabolismo , Perfilação da Expressão Gênica , Esquizofrenia/genética , Esquizofrenia/metabolismo , TranscriptomaRESUMO
Background: Discoidin domain receptor 1 (DDR1) signaling plays a critical role in various cellular functions. Increased DDR1 expression has been shown in different human cancers. t-DARPP is a truncated isoform of DARPP-32, and its upregulation promotes cell survival and migration. Most lung cancer patients have non-small cell lung cancer (NSCLC), and their survival rate is low. Therefore, it is necessary to study new and effective targeted therapies. Increased t-DARPP expression in NSCLC patients is associated with patient survival and can act as a prognostic marker correlated with increasing stages of NSCLC. The current study aimed to evaluate alteration in DDR1 expression and its effects on t-DARPP expression in NSCLC. Methods: Two human lung adenocarcinoma cell lines, A549 and Calu-3, were treated with collagen type I and transfected with DDR1 siRNA. The relative expression of DDR1 and t-DARPP was evaluated using qRT-PCR. Results: The results indicated that collagen type I could stimulate DDR1 expression in NSCLC cells. Also, DDR1 upregulation resulted in a significant increase in t-DARPP expression. In contrast, suppression of DDR1 expression significantly decreased t-DARPP expression. Conclusion: Our findings propose that modification in the expression of DDR1, caused by collagen type I and siRNA, might influence the expression of t-DARPP in NSCLC that is linked to NSCLC progression. Moreover, this alteration could potentially serve as an innovative target for therapeutic intervention.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptor com Domínio Discoidina 1/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Colágeno Tipo I , RNA Interferente Pequeno , Movimento Celular/genéticaRESUMO
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.
Assuntos
Receptor com Domínio Discoidina 2 , Neoplasias , Adulto , Humanos , Receptor com Domínio Discoidina 2/genética , Receptor com Domínio Discoidina 2/metabolismo , Receptores Mitogênicos/genética , Receptores Mitogênicos/metabolismo , Ligação Proteica , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptores com Domínio Discoidina/genética , Neoplasias/genética , Colágeno/metabolismo , Receptor com Domínio Discoidina 1/genética , Receptor com Domínio Discoidina 1/metabolismo , Microambiente TumoralRESUMO
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.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Animais , Camundongos , Quinase 2 de Adesão Focal/metabolismo , Neoplasias Pancreáticas/patologia , Carcinoma Ductal Pancreático/patologia , Transdução de Sinais , Autofagia , Linhagem Celular Tumoral , Receptor com Domínio Discoidina 1/metabolismoRESUMO
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.
Assuntos
Receptor com Domínio Discoidina 1 , Receptores Proteína Tirosina Quinases , Receptor com Domínio Discoidina 1/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Mecanotransdução Celular , Células Endoteliais/metabolismo , Transdução de SinaisRESUMO
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.
Assuntos
Osteogênese , Receptores Mitogênicos , Receptores com Domínio Discoidina , Receptores Mitogênicos/genética , Receptores Mitogênicos/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Colágeno/metabolismo , Receptor com Domínio Discoidina 1/metabolismoRESUMO
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.
Assuntos
Lipoma , Lipossarcoma , Humanos , Receptor com Domínio Discoidina 1/genética , Receptor com Domínio Discoidina 1/metabolismo , Proliferação de Células , Diferenciação Celular , Lipossarcoma/tratamento farmacológico , Lipossarcoma/genéticaRESUMO
BACKGROUND: Despite recent advances in therapy modalities of colorectal cancer (CRC), it is still the third cause of cancer-related deaths worldwide. Thus, the search for new target therapies became mandatory. DDR1 is a collagen receptor that has a suggested role in cellular proliferation, tumor invasion, and metastasis. MATERIAL AND METHODS: Forty-eight cases of CRC, 20 of CR adenoma, and 8 cases of non-tumoral colonic tissue were subjected to immunohistochemistry by DDR1 and ß-catenin antibodies. Results were compared among the different studied groups and correlated with clinicopathologic data and available survival data. Also, the expression of both proteins was compared versus each other. Results were compared among the 3 studied groups and correlated with clinicopathologic and survival data. RESULTS: It revealed a stepwise increase of DDR1 expression among studied groups toward carcinoma (P = 0.006). DDR1 expression showed a direct association with stage D in the modified Dukes' staging system (P = 0.013), higher-grade histologic types (P = 0.008), and lymph node invasion (P = 0.028) but inverse correlation with the presence of intratumoral inflammatory response (TIR) (P = 0.001). The shortest OS was associated with strong intensity of DDR1 (P = 0.012). The DDR1 and ß-catenin expressions were significantly correlated (P = 0.028), and the combined expression of both was correlated with TNM staging (P = 0.017). CONCLUSION: DDR1 overexpression is a frequent feature in CRC and CR adenoma. DDR1 is a poor prognostic factor and a suppressor of the TIR. DDR1 and ß-catenin seem to have a synergistic action.
Assuntos
Adenoma , Carcinoma , Neoplasias Colorretais , Humanos , beta Catenina , Neoplasias Colorretais/patologia , Relevância Clínica , Prognóstico , Receptor com Domínio Discoidina 1RESUMO
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.
Assuntos
Receptor com Domínio Discoidina 1 , Bainha de Mielina , Oligodendroglia , Animais , Feminino , Masculino , Camundongos , Diferenciação Celular , Sistema Nervoso Central , Receptor com Domínio Discoidina 1/genética , Receptor com Domínio Discoidina 1/metabolismo , Camundongos Knockout , Bainha de Mielina/metabolismo , Neurogênese , Oligodendroglia/metabolismo , Receptores Proteína Tirosina Quinases/metabolismoRESUMO
BACKGROUND: Immune exclusion (IE) where tumors deter the infiltration of immune cells into the tumor microenvironment has emerged as a key mechanism underlying immunotherapy resistance. We recently reported a novel role of discoidin domain-containing receptor 1 (DDR1) in promoting IE in breast cancer and validated its critical role in IE using neutralizing rabbit monoclonal antibodies (mAbs) in multiple mouse tumor models. METHODS: To develop a DDR1-targeting mAb as a potential cancer therapeutic, we humanized mAb9 with a complementarity-determining region grafting strategy. The humanized antibody named PRTH-101 is currently being tested in a Phase 1 clinical trial. We determined the binding epitope of PRTH-101 from the crystal structure of the complex between DDR1 extracellular domain (ECD) and the PRTH-101 Fab fragment with 3.15 Å resolution. We revealed the underlying mechanisms of action of PRTH-101 using both cell culture assays and in vivo study in a mouse tumor model. RESULTS: PRTH-101 has subnanomolar affinity to DDR1 and potent antitumor efficacy similar to the parental rabbit mAb after humanization. Structural information illustrated that PRTH-101 interacts with the discoidin (DS)-like domain, but not the collagen-binding DS domain of DDR1. Mechanistically, we showed that PRTH-101 inhibited DDR1 phosphorylation, decreased collagen-mediated cell attachment, and significantly blocked DDR1 shedding from the cell surface. Treatment of tumor-bearing mice with PRTH-101 in vivo disrupted collagen fiber alignment (a physical barrier) in the tumor extracellular matrix (ECM) and enhanced CD8+ T cell infiltration in tumors. CONCLUSIONS: This study not only paves a pathway for the development of PRTH-101 as a cancer therapeutic, but also sheds light on a new therapeutic strategy to modulate collagen alignment in the tumor ECM for enhancing antitumor immunity.
Assuntos
Anticorpos Monoclonais , Receptor com Domínio Discoidina 1 , Neoplasias , Animais , Camundongos , Colágeno/metabolismo , Receptor com Domínio Discoidina 1/metabolismo , Matriz Extracelular/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Microambiente Tumoral , Anticorpos Monoclonais/farmacologiaRESUMO
Background: Two fundamental challenges in the current therapeutic approach for central nervous system tumors are the tumor heterogeneity and the absence of specific treatments and biomarkers that selectively target the tumor tissue. Therefore, we aimed to investigate the potential relationship between discoidin domain receptor 1 (DDR1) expression and the prognosis and characteristics of glioma patients. Materials and Methods: Tissue and serum samples from 34 brain tumor patients were evaluated for DDR1 messenger ribonucleic acid levels in comparison to 10 samples from the control group, and Kaplan-Meier survival analysis has performed. Results: DDR1 expression was observed in both tissue and serum samples of the patient and control groups. DDR1 expression levels in tissue and serum samples from patients were higher in comparison to the control group, although not statistically significant (P > 0.05). A significant correlation between tumor size and DDR1 serum measurements at the level of 0.370 was reported (r = 0.370; P = 0.034). The levels of DDR1 in serum showed a positive correlation with the increasing size of tumor. The results of the 5-year survival analysis depending on the DDR1 tissue levels showed a significantly higher survival rate (P = 0.041) for patients who have DDR1 tissue levels above cutoff value. Conclusions: DDR1 expression was significantly higher among brain tumor tissues and serum samples and its levels showed a positive correlation with the increased size of tumor. This study can be a starting point, since it investigated and indicated, for the first time, that DDR1 can be a novel therapeutic and prognostic target for aggressive high-grade gliomas.
Assuntos
Neoplasias Encefálicas , Glioma , Humanos , Receptor com Domínio Discoidina 1/genética , Receptor com Domínio Discoidina 1/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Biomarcadores , Glioma/diagnóstico , Glioma/genética , Neoplasias Encefálicas/genéticaRESUMO
Disk-like domain receptor 1 (DDR1) is a crucial regulator of pro-inflammatory mediators and matrix-degrading enzymes. Although mounting evidence supports a vital role for DDR1 in the tumorigenesis of some cancers, no pan-cancer analysis of DDR1 has been reported. Therefore, we aimed to explore the prognostic value of DDR1 in 33 cancer types and investigate its potential immune function. We used a range of bioinformatics approaches to explore the potential carcinogenic role of DDR1 in multiple cancers. We found that DDR1 was expressed at high levels in most cancers. DDR1 expression was positively or negatively associated with prognosis in different cancers. DDR1 expression was significantly associated with DNA methylation in 8 cancers, while there was a correlation between DDR1 expression and RNA methylation-related genes and mismatch repair gene in most cancers. Furthermore, DDR1 expression was significantly associated with microsatellite instability in 6 cancers and tumor mutation burden in 11 cancers. In addition, DDR1 expression was also significantly correlated with immune cell infiltration, tumor microenvironment, immune-related genes, and drug resistance in various cancers. In conclusion, DDR1 can serve as a potential therapeutic target and prognostic marker for various malignancies due to its vital role in tumorigenesis and tumor immunity.
Assuntos
Neoplasias , Humanos , Prognóstico , Neoplasias/genética , Carcinogênese , Carcinógenos , Transformação Celular Neoplásica , Resistência a Medicamentos , Microambiente Tumoral/genética , Biomarcadores Tumorais/genética , Receptor com Domínio Discoidina 1/genéticaRESUMO
Cancer stem cells (CSCs) are a minority population of cancer cells with stemness and multiple differentiation potentials, leading to cancer progression and therapeutic resistance. However, the concrete mechanism of CSCs in hepatocellular carcinoma (HCC) remains obscure. We found that in advanced HCC tissues, collagen I was upregulated, which is consistent with the expression of its receptor DDR1. Accordingly, high collagen I levels accompanied by high DDR1 expression are associated with poor prognoses in patients with HCC. Collagen I-induced DDR1 activation enhanced HCC cell stemness in vitro and in vivo. Mechanistically, DDR1 interacts with CD44, which acts as a co-receptor that amplifies collagen I-induced DDR1 signaling, and collagen I-DDR1 signaling antagonized Hippo signaling by facilitating the recruitment of PP2AA to MST1, leading to exaggerated YAP activation. The combined inhibition of DDR1 and YAP synergistically abrogated HCC cell stemness in vitro and tumorigenesis in vivo. A radiomic model based on T2 weighted images can noninvasively predict collagen I expression. These findings reveal the molecular basis of collagen I-DDR1 signaling inhibiting Hippo signaling and highlight the role of CD44/DDR1/YAP axis in promoting cancer cell stemness, suggesting that DDR1 and YAP may serve as novel prognostic biomarkers and therapeutic targets in HCC.