Explore the vast range of titles available.

Immune exclusion predicts poor patient outcomes in multiple malignancies, including triple-negative breast cancer (TNBC) 1 . The extracellular matrix (ECM) contributes to immune exclusion 2 . However, strategies to reduce ECM abundance are largely ineffective or generate undesired outcomes 3 , 4 . Here we show that discoidin domain receptor 1 (DDR1), a collagen receptor with tyrosine kinase activity 5 , instigates immune exclusion by promoting collagen fibre alignment. Ablation of Ddr1 in tumours promotes the intratumoral penetration of T cells and obliterates tumour growth in mouse models of TNBC. Supporting this finding, in human TNBC the expression of DDR1 negatively correlates with the intratumoral abundance of anti-tumour T cells. The DDR1 extracellular domain (DDR1-ECD), but not its intracellular kinase domain, is required for immune exclusion. Membrane-untethered DDR1-ECD is sufficient to rescue the growth of Ddr1 -knockout tumours in immunocompetent hosts. Mechanistically, the binding of DDR1-ECD to collagen enforces aligned collagen fibres and obstructs immune infiltration. ECD-neutralizing antibodies disrupt collagen fibre alignment, mitigate immune exclusion and inhibit tumour growth in immunocompetent hosts. Together, our findings identify a mechanism for immune exclusion and suggest an immunotherapeutic target for increasing immune accessibility through reconfiguration of the tumour ECM. In mouse models of triple-negative breast cancer, the extracellular domain of the collagen receptor DDR1 has a role in tumour defence against the immune system, by aligning collagen fibres to obstruct immune infiltration.

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses and spreads by metastasis to the liver 1 . Cancer-associated fibroblasts, the extracellular matrix and type I collagen (Col I) support 2 , 3 or restrain the progression of PDAC and may impede blood supply and nutrient availability 4 . The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers to escape nutrient limitation, remain poorly understood. Here we show that matrix-metalloprotease-cleaved Col I (cCol I) and intact Col I (iCol I) exert opposing effects on PDAC bioenergetics, macropinocytosis, tumour growth and metastasis. Whereas cCol I activates discoidin domain receptor 1 (DDR1)–NF-κB–p62–NRF2 signalling to promote the growth of PDAC, iCol I triggers the degradation of DDR1 and restrains the growth of PDAC. Patients whose tumours are enriched for iCol I and express low levels of DDR1 and NRF2 have improved median survival compared to those whose tumours have high levels of cCol I, DDR1 and NRF2. Inhibition of the DDR1-stimulated expression of NF-κB or mitochondrial biogenesis blocks tumorigenesis in wild-type mice, but not in mice that express MMP-resistant Col I. The diverse effects of the tumour stroma on the growth and metastasis of PDAC and on the survival of patients are mediated through the Col I–DDR1–NF-κB–NRF2 mitochondrial biogenesis pathway, and targeting components of this pathway could provide therapeutic opportunities. Cleaved and intact type I collagen have different effects on pancreatic ductal adenocarcinoma (PDAC), and remodelling of type I collagen—mediated through DDR1 signalling—is a prognostic indicator for the survival of patients with PDAC.

Hepatocellular carcinoma (HCC), the fourth leading cause of cancer mortality worldwide, develops almost exclusively in patients with chronic liver disease and advanced fibrosis 1 , 2 . Here we interrogated functions of hepatic stellate cells (HSCs), the main source of liver fibroblasts 3 , during hepatocarcinogenesis. Genetic depletion, activation or inhibition of HSCs in mouse models of HCC revealed their overall tumour-promoting role. HSCs were enriched in the preneoplastic environment, where they closely interacted with hepatocytes and modulated hepatocarcinogenesis by regulating hepatocyte proliferation and death. Analyses of mouse and human HSC subpopulations by single-cell RNA sequencing together with genetic ablation of subpopulation-enriched mediators revealed dual functions of HSCs in hepatocarcinogenesis. Hepatocyte growth factor, enriched in quiescent and cytokine-producing HSCs, protected against hepatocyte death and HCC development. By contrast, type I collagen, enriched in activated myofibroblastic HSCs, promoted proliferation and tumour development through increased stiffness and TAZ activation in pretumoural hepatocytes and through activation of discoidin domain receptor 1 in established tumours. An increased HSC imbalance between cytokine-producing HSCs and myofibroblastic HSCs during liver disease progression was associated with increased HCC risk in patients. In summary, the dynamic shift in HSC subpopulations and their mediators during chronic liver disease is associated with a switch from HCC protection to HCC promotion. Subpopulations of cytokine-producing and myofibroblastic hepatic stellate cells, identified by single-cell RNA sequencing, protect against or promote the development of hepatocellular carcinoma via high expression of hepatocyte growth factor or type I collagen, respectively..

The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. Here, we show that nilotinib, a clinically approved drug for chronic myeloid leukaemia, strongly inhibits human CRC cell invasion in vitro and reduces their metastatic potential in intrasplenic tumour mouse models. Nilotinib acts by inhibiting the kinase activity of DDR1, a receptor tyrosine kinase for collagens, which we identified as a RAS‐independent inducer of CRC metastasis. Using quantitative phosphoproteomics, we identified BCR as a new DDR1 substrate and demonstrated that nilotinib prevents DDR1‐mediated BCR phosphorylation on Tyr177, which is important for maintaining β‐catenin transcriptional activity necessary for tumour cell invasion. DDR1 kinase inhibition also reduced the invasion of patient‐derived metastatic and circulating CRC cell lines. Collectively, our results indicate that the targeting DDR1 kinase activity with nilotinib may be beneficial for patients with mCRC. Synopsis The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. Targeting the receptor for collagens DDR1 by nilotinib inhibits mCRC cells properties and paves the way to a new therapeutic strategy for mCRC. DDR1 tyrosine kinase activity promotes colorectal cancer cell invasion and metastatic properties in nude mice. BCR is a central substrate of DDR1. DDR1 activation maintains a high level of β‐catenin transcriptional activity necessary for cell invasion and metastatic progression. DDR1 pharmacological inhibition by nilotinib inhibits colorectal cancer cell invasion and metastatic properties in nude mice. Nilotinib may be of clinical interest for treatment of metastatic colorectal cancer. Graphical Abstract The clinical management of metastatic colorectal cancer (mCRC) faces major challenges. Targeting the receptor for collagens DDR1 by nilotinib inhibits mCRC cells properties and paves the way to a new therapeutic strategy for mCRC.

Background C1q has been reported to reveal complement-independent roles in immune and non-immune cells. C1q binds to its specific receptors to regulate distinct functions that rely on the environment and cell types. Discoidin domain receptor 2 (DDR2) is activated by collagen and functions in wound healing by controlling matrix metalloproteinase (MMP) expression. Since C1q exhibits a collagen-like structure, we hypothesized that C1q might engage DDR2 to regulate wound healing and extracellular matrix (ECM) remodeling. Methods Cell-based assay, proximity ligation assay, ELISA, and surface plasmon analysis were utilized to investigate DDR2 and C1q binding. We also investigate the C1q-mediated in vitro wound healing ability using the human fibrosarcoma cell line, HT1080. Results C1q induced the phosphorylation of DDR2, p38 kinase, and ERK1/2. C1q and DDR2 binding improved cell migration and induced MMP2 and MMP9 expression. DDR2-specific shRNA reduced C1q-mediated cell migration for wound healing. Conclusions C1q is a new DDR2 ligand that promotes wound healing. These findings have therapeutic implications in wound healing-related diseases.

Discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family, and its ligand is collagen. Previous studies demonstrated that DDR1 is highly expressed in many tumors. However, its role in hepatocellular carcinoma (HCC) remains obscure. In this study, we found that DDR1 was upregulated in HCC tissues, and the expression of DDR1 in TNM stage II-IV was higher than that in TNM stage I in HCC tissues, and high DDR1 expression was associated with poor prognosis. Gene expression analysis showed that DDR1 target genes were functionally involved in HCC metastasis. DDR1 positively regulated the migration and invasion of HCC cells and promoted lung metastasis. Human Phospho-Kinase Array showed that DDR1 activated ERK/MAPK signaling pathway. Mechanically, DDR1 interacted with ARF6 and activated ARF6 through recruiting PSD4. The kinase activity of DDR1 was required for ARF6 activation and its role in metastasis. High expression of PSD4 was associated with poor prognosis in HCC. In summary, our findings indicate that DDR1 promotes HCC metastasis through collagen induced DDR1 signaling mediated PSD4/ARF6 signaling, suggesting that DDR1 and ARF6 may serve as novel prognostic biomarkers and therapeutic targets for metastatic HCC.

Discoidin domain receptor 1 (DDR1), a collagen-binding receptor tyrosine kinase, plays a key role in extracellular matrix remodeling, tumor progression, and immune evasion. However, DDR1’s comprehensive role across diverse cancers and its therapeutic potential in immune-resistant tumors remain poorly defined. We performed a pan-cancer analysis integrating bulk transcriptomic datasets, single-cell RNA sequencing, and pathway enrichment to evaluate DDR1 expression, genetic alterations, and its associations with immune cell infiltration and clinical outcomes. DDR1 was consistently overexpressed in 21 cancer types, correlating with poor prognosis and reduced immune cell infiltration. Mechanistically, DDR1 promoted collagen remodeling, immune exclusion, and upregulated immunosuppressive pathways. Single-cell analysis in pancreatic ductal adenocarcinoma (PDAC) revealed DDR1-high ductal cells associated with reduced cytotoxic T cell infiltration and increased regulatory T cell populations. Therapeutic blockade of DDR1 in an immunocompetent KPC mouse model of PDAC disrupted collagen architecture, enhanced CD8+ T cell infiltration, and improved responses to chemotherapy, highlighting a direct link between DDR1 inhibition and immune reactivation. These findings establish DDR1 as a key mediator of collagen-driven immune resistance and a promising therapeutic target for overcoming immune exclusion, especially in PDAC and other collagen-rich solid tumors.

KRAS-mutant lung adenocarcinoma remains without effective targeted therapies for most patients, particularly those with non-G12C alleles or resistance to KRASG12C inhibitors. RAF1 is essential for KRAS-driven tumor maintenance through kinase-independent survival functions, making it an attractive candidate for targeted protein degradation. However, the therapeutic impact and safety of co-targeting RAF1 with related kinases remain unclear. We used dual-recombinase genetically engineered mouse models of Kras+/G12V;Trp53-/- lung cancer to evaluate the effects of Raf1 ablation alone or in combination with Araf, Egfr, or Ddr1. Lung tumors were initiated by intranasal Ad5-CMV-FLPo delivery and allowed to reach CT-detectable size before inducing systemic gene deletion via tamoxifen-activated CreERT2. Tumor burden was monitored by longitudinal CT imaging and classified using RECIST-like criteria. Toxicity was assessed by body weight monitoring, histopathology of major organs, and survival analysis. Raf1 deletion induced robust tumor regression within two months, in more than 60% of lesions. Araf ablation alone or combined with Raf1 did not affect tumor initiation, progression, or regression rates. Similarly, neither genetic nor pharmacological EGFR inhibition (afatinib) improved responses to Raf1 ablation. Ddr1 co-deletion also failed to enhance therapeutic efficacy and slightly reduced response rates. None of the dual-targeting strategies increased systemic toxicity. RAF1 is a key, non-redundant vulnerability in KRAS-driven lung adenocarcinoma. Co-targeting ARAF, EGFR, or DDR1 provides no additional therapeutic benefit in established disease. The absence of adverse effects from ARAF co-deletion suggests that RAF1 degraders with partial cross-activity towards ARAF are likely to be safe. These findings provide a strong preclinical rationale for developing RAF1-targeted degradation as a monotherapy for these malignancies.

We have developed a deep generative model, generative tensorial reinforcement learning (GENTRL), for de novo small-molecule design. GENTRL optimizes synthetic feasibility, novelty, and biological activity. We used GENTRL to discover potent inhibitors of discoidin domain receptor 1 (DDR1), a kinase target implicated in fibrosis and other diseases, in 21 days. Four compounds were active in biochemical assays, and two were validated in cell-based assays. One lead candidate was tested and demonstrated favorable pharmacokinetics in mice. A machine learning model allows the identification of new small-molecule kinase inhibitors in days.

Pulmonary hypertension (PH) is a multifaceted condition characterized by elevated pulmonary arterial pressure, which can result in right ventricular dysfunction and failure. Disorders of lung development can present with secondary PH, which is a leading cause of mortality in infants with bronchopulmonary dysplasia (BPD). DDR1 (discoidin domain receptor 1) is a collagen-binding receptor that regulates tissue fibrosis and inflammation and controls cellular growth and migration. However, the roles of DDR1 in lung development or the pathogenesis of PH are unknown. Studying mice with a DDR1 deletion (Ddr1−/−), we have noted 35% mortality between 1 and 4 months of age, and we demonstrate that DDR1 deficiency results in reduced right ventricular contractility and muscularization of distal pulmonary arteries, consistent with PH. Pathology analysis revealed enlarged alveolar spaces in Ddr1−/− mice by Postnatal Day 7, consistent with impaired alveolar development. Gene expression analysis showed that Ddr1−/− mice have reduced concentrations of alveologenesis factors and epithelial-to-mesenchymal transition markers. Mechanistic studies in vitro confirmed that DDR1 mediated epithelial-to-mesenchymal transition, migration, and growth of alveolar epithelial cells. Taken together, these data suggest that DDR1 plays important roles mediating alveolarization during lung development. Our studies also describe a new model of spontaneous PH and bronchopulmonary dysplasia in mice.