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Epithelial-to-mesenchymal transition (EMT) regulates tumour initiation, progression, metastasis and resistance to anti-cancer therapy 1 – 7 . Although great progress has been made in understanding the role of EMT and its regulatory mechanisms in cancer, no therapeutic strategy to pharmacologically target EMT has been identified. Here we found that netrin-1 is upregulated in a primary mouse model of skin squamous cell carcinoma (SCC) exhibiting spontaneous EMT. Pharmacological inhibition of netrin-1 by administration of NP137, a netrin-1-blocking monoclonal antibody currently used in clinical trials in human cancer (ClinicalTrials.gov identifier NCT02977195 ), decreased the proportion of EMT tumour cells in skin SCC, decreased the number of metastases and increased the sensitivity of tumour cells to chemotherapy. Single-cell RNA sequencing revealed the presence of different EMT states, including epithelial, early and late hybrid EMT, and full EMT states, in control SCC. By contrast, administration of NP137 prevented the progression of cancer cells towards a late EMT state and sustained tumour epithelial states. Short hairpin RNA knockdown of netrin-1 and its receptor UNC5B in EPCAM + tumour cells inhibited EMT in vitro in the absence of stromal cells and regulated a common gene signature that promotes tumour epithelial state and restricts EMT. To assess the relevance of these findings to human cancers, we treated mice transplanted with the A549 human cancer cell line—which undergoes EMT following TGFβ1 administration 8 , 9 —with NP137. Netrin-1 inhibition decreased EMT in these transplanted A549 cells. Together, our results identify a pharmacological strategy for targeting EMT in cancer, opening up novel therapeutic interventions for anti-cancer therapy. Netrin-1 is upregulated in cancer models that undergo spontaneous epithelial-to-mesenchymal transition, and its targeting blocks the progression of tumour cells to a late mesenchymal state, suggesting possible therapeutic applications.

Joint pain is the defining symptom of osteoarthritis (OA) but its origin and mechanisms remain unclear. Here, we investigated an unprecedented role of osteoclast-initiated subchondral bone remodeling in sensory innervation for OA pain. We show that osteoclasts secrete netrin-1 to induce sensory nerve axonal growth in subchondral bone. Reduction of osteoclast formation by knockout of receptor activator of nuclear factor kappa-B ligand (Rankl) in osteocytes inhibited the growth of sensory nerves into subchondral bone, dorsal root ganglion neuron hyperexcitability, and behavioral measures of pain hypersensitivity in OA mice. Moreover, we demonstrated a possible role for netrin-1 secreted by osteoclasts during aberrant subchondral bone remodeling in inducing sensory innervation and OA pain through its receptor DCC (deleted in colorectal cancer). Importantly, knockout of Netrin1 in tartrate-resistant acid phosphatase-positive (TRAP-positive) osteoclasts or knockdown of Dcc reduces OA pain behavior. In particular, inhibition of osteoclast activity by alendronate modifies aberrant subchondral bone remodeling and reduces innervation and pain behavior at the early stage of OA. These results suggest that intervention of the axonal guidance molecules (e.g., netrin-1) derived from aberrant subchondral bone remodeling may have therapeutic potential for OA pain.

Spinal pain is a major clinical problem, however, its origins and underlying mechanisms remain unclear. Here we report that in mice, osteoclasts induce sensory innervation in the porous endplates which contributes to spinal hypersensitivity in mice. Sensory innervation of the porous areas of sclerotic endplates in mice was confirmed. Lumbar spine instability (LSI), or aging, induces spinal hypersensitivity in mice. In these conditions, we show that there are elevated levels of PGE2 which activate sensory nerves, leading to sodium influx through Na v 1.8 channels. We show that knockout of PGE2 receptor 4 in sensory nerves significantly reduces spinal hypersensitivity. Inhibition of osteoclast formation by knockout Rankl in the osteocytes significantly inhibits LSI-induced porosity of endplates, sensory innervation, and spinal hypersensitivity. Knockout of Netrin-1 in osteoclasts abrogates sensory innervation into porous endplates and spinal hypersensitivity. These findings suggest that osteoclast-initiated porosity of endplates and sensory innervation are potential therapeutic targets for spinal pain. Spinal pain is a major clinical problem. Here the authors show that osteoclasts create porous area of endplates of the vertebrae and sensory innervation of porous endplates by Netrin-1 release from osteoclasts mediates PGE2-induced spinal hypersensitivity in mice.

Abdominal aortic aneurysms (AAA) are characterized by extensive extracellular matrix (ECM) fragmentation and inflammation. However, the mechanisms by which these events are coupled thereby fueling focal vascular damage are undefined. Here we report through single-cell RNA-sequencing of diseased aorta that the neuronal guidance cue netrin-1 can act at the interface of macrophage-driven injury and ECM degradation. Netrin-1 expression peaks in human and murine aneurysmal macrophages. Targeted deletion of netrin-1 in macrophages protects mice from developing AAA. Through its receptor neogenin-1, netrin-1 induces a robust intracellular calcium flux necessary for the transcriptional regulation and persistent catalytic activation of matrix metalloproteinase-3 (MMP3) by vascular smooth muscle cells. Deficiency in MMP3 reduces ECM damage and the susceptibility of mice to develop AAA. Here, we establish netrin-1 as a major signal that mediates the dynamic crosstalk between inflammation and chronic erosion of the ECM in AAA. Abdominal aortic aneurysms (AAA) are characterized by extensive extracellular matrix degradation. Here Hadi et al. identify a netrin-1/neogenin-based crosstalk between macrophages and vascular smooth muscle cells (VSMCs), leading to the secretion of the matrix metalloproteinase MMP-3 by VSMCs and subsequent matrix degradation in AAA lesions.

Netrin-1 signaling is an essential prototypical neuronal guidance mechanism during embryonic development that also regulates tumor cell survival in a variety of adult cancer entities. In line with these data, a monoclonal netrin-1 blocking antibody (anti-netrin-1 mAb/NP137) has been preclinically developed and netrin-1 blockade has recently been investigated in phase 1 and 2 clinical trials in several adult cancers. Here, we investigate the role of netrin-1 in the most common malignant pediatric brain cancer, Medulloblastoma. Interestingly, we find that netrin-1 is upregulated in medulloblastoma subgroups associated with developmental dysregulation, in particular in medulloblastoma with Sonic Hedgehog (SHH) activation. First, we demonstrate that genetic deletion of netrin-1 or systemic treatment with the clinical-stage anti-netrin-1 blocking antibody significantly reduces tumor growth in vivo in various orthotopic models of SHH medulloblastomas. Second, in vitro and in vivo, we unexpectedly uncover that SHH medulloblastomas treated with an SHH-inhibitor targeting Smoothened (SMO) increase netrin-1 expression, paving the way for combinatorial therapy. In line with that, we next show that netrin-1 blockade potentiates the efficacy of SMO inhibitor therapy in vivo. Together, our data indicate that, netrin-1 blockade, used as monotherapy or in combination with SMO inhibitors, is a promising therapeutic strategy in SHH medulloblastomas. Despite being an important driver of a subset of medulloblastomas, efforts to therapeutically target Sonic Hedgehog (SHH) signaling, such as with the use of Smoothened (SMO) inhibitors, have had limited success. Here, the authors find that SHH medulloblastomas are sensitive to netrin-1 inhibition and investigate netrin-1 as a mechanism of resistance to SMO inhibition.

The signal pathways mediated by axon guiding molecule netrin-1 (NTN1) are transduced via its several membrane-bound receptors that include deleted in colorectal cancer (DCC), UNC5 (A–D), neogenin 1 (Neo1), melanoma cell adhesion molecule (MCAM), and Down syndrome cell adhesion molecule (DSCAM). Most of these genes play a role in the occurrence and progression of some solid tumors. Sufficient systematic studies have not been performed on the expression characteristics of the role of NTN1 and its receptors in the context of pan-cancer. Based on data from 10,437 subjects with 33 types of solid tumors in The Cancer Genome Atlas, we systematically analyzed the tumor molecular biological characteristics of NTN1 and its receptors through bioinformatics. Candidate small-molecule drugs were identified based on molecular docking analysis. Netrin-1 and its receptors exhibited stereotypical genetic alterations in tumor-suppressor genes or oncogenes. Promoter methylation and miRNA-mediated post-transcriptional inhibition likely represent the primary regulatory mechanisms, whereas the promotion of epithelial-mesenchymal transition (EMT) emerges as a conserved cellular function. we predicted potential small-molecule drugs that could bind to Netrin1 receptors. NTN1 and its receptors can be used as potential targets for tumor immunotherapy. Our results showed the important cancer biological functions of NTN1 and its receptors and their transformational value as candidate tumor biomarkers. This study also showed some critical potential immune-related therapeutic targets and provided a basis for future studies on their role in clinical immunotherapy.

Background Inflammation is increasingly recognized in the pathogenesis of diabetic neuropathy (DN). Circulating miR‐27a‐3p levels are closely related to inflammation and increased in patients with diabetic nephropathy and retinopathy. miR‐27a‐3p has a predicted binding site in the 3 UTR of Netrin‐1 mRNA, an anti‐inflammatory nerve growth factor whose levels correlate with small nerve fiber loss in patients with DN. Methods Eighty‐two participants with (DN+) and without (DN‐) small nerve fiber damage and 45 healthy controls underwent measurement of plasma miR‐27a‐3p, PBMC levels of NF‐kB and NLRP3, serum Netrin‐1, TNFα, IL‐1β, and IL‐10 levels. Results Corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) were significantly lower in the DN‐ and DN+ groups compared to controls (p < 0.001). Plasma miR‐27a‐3p and PBMC NF‐kB and NLRP3 expression were significantly higher in the DN+ group, and miR‐27a‐3p identified DN+ with an area under the curve (AUC) of 89%. Serum Netrin‐1 and IL‐10 levels were lower, while TNFα and IL‐1β levels were higher in the DN+ group. miR‐27a‐3p levels correlated negatively with CNFL and Netrin‐1 and positively with NF‐kB and NLRP3. Conclusion miR‐27a‐3p levels are elevated in subjects with DN and correlate with markers of inflammation, Netrin‐1, and corneal nerve loss. miR‐27a‐3p could be a biomarker for DN, and miR‐27a‐3p/Netrin‐1 crosstalk may be a promising therapeutic target for DN.

Fibrosis is a macrophage-driven process of uncontrolled extracellular matrix accumulation. Neuronal guidance proteins such as netrin-1 promote inflammatory scarring. We found that macrophage-derived netrin-1 stimulates fibrosis through its neuronal guidance functions. In mice, fibrosis due to inhaled bleomycin engendered netrin-1-expressing macrophages and fibroblasts, remodeled adrenergic nerves, and augmented noradrenaline. Cell-specific knockout mice showed that collagen accumulation, fibrotic histology, and nerve-associated endpoints required netrin-1 of macrophage but not fibroblast origin. Adrenergic denervation; haploinsufficiency of netrin-1's receptor, deleted in colorectal carcinoma; and therapeutic α1 adrenoreceptor antagonism improved collagen content and histology. An idiopathic pulmonary fibrosis (IPF) lung microarray data set showed increased netrin-1 expression. IPF lung tissues were enriched for netrin-1+ macrophages and noradrenaline. A longitudinal IPF cohort showed improved survival in patients prescribed α1 adrenoreceptor blockade. This work showed that macrophages stimulate lung fibrosis via netrin-1-driven adrenergic processes and introduced α1 blockers as a potentially new fibrotic therapy.

The ɛ4 allele of the apolipoprotein E (APOE) gene stands as the most significant genetic risk factor for Alzheimer’s disease (AD), although the underlying mechanism linking APOE to the disease remains elusive. Netrin-1, has been found to inhibit Aβ production, reduce neuroinflammation, and regulate synaptic plasticity, thereby playing a role in AD. Recent reports suggest that Netrin-1 could be a key protein connecting APOE ɛ4 with Aβ and tau tangles. This study aims to investigate whether APOE regulates the expression or function of Netrin-1, thus influencing the risk of developing AD. The serum levels of Netrin-1 were notably reduced in patients with AD compared to healthy individuals, whereas interleukin-6 (IL-6) concentrations were higher in the AD group. patients harboring the APOE ε4 allele exhibited a more pronounced decrease in Netrin-1 compared to those with other APOE genotypes. Furthermore, a correlation was observed between Netrin-1 concentrations and APOE allelic variations. Our results imply that Netrin-1 is a key player in the cognitive decline observed in AD and potentially contributes to the APOE-driven cognitive impairment process. This association is tightly linked to inflammatory factors, suggesting that Netrin-1 may serve as a crucial biomarker for the prognosis and therapeutic intervention of AD.

Axon guidance molecules direct growing axons toward their targets, assembling the intricate wiring of the nervous system. One of these molecules, Netrin-1, and its receptor, DCC (deleted in colorectal cancer), has profound effects, in laboratory animals, on the adolescent expansion of mesocorticolimbic pathways, particularly dopamine. Now, a rapidly growing literature suggests that (1) these same alterations could occur in humans, and (2) genetic variants in Netrin-1 and DCC are associated with depression, schizophrenia, and substance use. Together, these findings provide compelling evidence that Netrin-1 and DCC influence mesocorticolimbic-related psychopathological states that emerge during adolescence.