Endosomal trafficking bypassed by RAB5B-CD109 interplay promotes axonogenesis in KRAS-mutant pancreatic cancer
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ABSTRACT:
PROVIDER: PRJNA1055921 | ENA |
REPOSITORIES: ENA
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Project description:Perineural invasion (PNI) represents a unique biological feature causing the poor prognosis of pancreatic ductal adenocarcinoma (PDAC), especially with KRAS mutation. Extracellular vesicle (EVs)-packaged circRNAs function as essential mediator for tumor microenviroment communication to trigger PDAC cells invading into the surrounding regions and lead to distant metastasis. However, the regulatory mechanism of exosomal circRNA in PNI of KRAS-mutated PDAC has not been elucidated. Herein, we identified an KRASG12D-mutation responsive exosomal circRNA-circPNIT, which was positively correlated with PNI of PDAC. Functionally, KRASG12D PDAC-derived EV-packaged circPNIT promotes axonogenesis and PNI both in vitro and in vivo. Mechanistically, circPNIT-mediated Rab5B-CD109 interplay bypassed traditional endosomal trafficking to anchor Rab5B in the lipid rafts of multivescular body and fostered the secretion of circPNIT as a cargo of CD109+EVs. Subsequently, CD109+EVs achieved the targeted delivery of circPNIT to neurons by recognizing their surface receptor TRPV1 and facilitated DSCAML1 transcription-induced axonogenesis, which in turn enhanced the PNI by activating GFRα1/RET pathway. Importantly, we established an engineered si-cirPNIT-loaded CD109+EVs to dramatically inhibit PNI of PDAC in a KRASG12D/+ Trp53R172H/+ Pdx-1-Cre mice model. Collectively, Our findings highlight the mechanism underlying EV-packaed circRNA mediating PNI of KRAS mutated-PDAC dependent of a Rab5B endosomal bypass, supporting circPINT as an effective target for the treatment of neuro-metastatic PDAC
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Project description:CD109 is a glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed in several types of human cancers, particularly squamous cell carcinomas. We previously reported that CD109-deficient mice exhibit epidermal hyperplasia and chronic skin inflammation. Although we found that CD109 regulates differentiation of keratinocytes in vivo, the function of CD109 in tumorigenesis remains unknown. In this study, we investigated the role of CD109 in skin tumorigenesis using a two-stage carcinogenesis model in CD109-deficient mice with chronic skin inflammation.
2016-09-28 | GSE87390 | GEO
Project description:PDGFRa signaling regulates Srsf3 transcript binding to affect PI3K signaling and endosomal trafficking (eCLIP)
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Project description:Loss of the Sortilin-related receptor 1 (SORL1) gene seems to act as a causal event for Alzheimer’s disease (AD). Recent studies have established that loss of SORL1, as well as mutations in autosomal dominant AD genes APP and PSEN1/2, pathogenically converge by swelling early endosomes, AD’s cytopathological hallmark. Acting together with the retromer trafficking complex, SORL1 has been shown to regulate the recycling of the amyloid precursor protein (APP) out of the endosome, contributing to endosomal swelling and to APP misprocessing. We hypothesized that SORL1 plays a broader role in neuronal endosomal recycling and used human induced pluripotent stem cell derived neurons (hiPSC-Ns) to test this hypothesis. In SORL1 deficient (SORL1KO) cell lines, we map the trafficking of the glutamate receptor and the BDNF neurotrophic receptor, two kinds of transmembrane proteins that depend on endosomal recycling and that are linked to AD pathophysiology. We find that as with APP, SORL1 is required for efficient endosomal recycling of the glutamate receptor AMPA1 (GLUA1) and the BDNF receptor Tropomyosin-related kinase B (TRKB). Next, we used cell lines engineered to overexpress SORL1 and find that increased SORL1 expression enhances recycling for APP and GLUA1. Finally, we performed an unbiased transcriptomic screen of SORL1KO neurons and the data further support SORL1’s role in endosomal recycling. We observed altered expression networks that regulate cell surface trafficking and neurotrophic signaling. Collectively, and together with other recent observations, these findings suggest that SORL1 is a key and broad regulator of retromer-dependent endosomal recycling in neurons, a conclusion that has both pathogenic and therapeutic implications.
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Project description:Glioma stem cells (GSCs) drive propagation and therapeutic resistance of glioblastomas, the most aggressive diffuse brain tumor. However, the molecular mechanisms that maintain the stemness and promote therapy resistance remain poorly understood. Here we study CD109 – STAT3 axis as crucial for the maintenance of stemness and tumorigenicity of GSCs and as a mediator of chemoresistance. Mechanistically, CD109 physically interacts with glycoprotein 130 (GP130) to promote activation of the IL-6/STAT3 pathway in GSCs. Genetic depletion of CD109 abolished the stemness and self-renewal of GSCs and impaired tumorigenicity. Loss of stemness was accompanied with a phenotypic shift of GSCs to more differentiated astrocytic-like cells. Importantly, genetic or pharmacologic targeting of CD109 – STAT3 axis sensitized the GSCs to chemotherapy suggesting that targeting CD109 – STAT3 axis has potential to overcome therapy resistance in glioblastoma.
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Project description:CD109 is a glycosylphosphatidylinositol-anchored glycoprotein highly expressed in several types of human malignant tumors including lung cancers. We investigated the in vivo functions of CD109 protein in malignant lung tumors. CD109+/+ and CD109-/- K-ras[LSL-G12D/+];p53[fl/fl] (KP) mice were sacrificed at 20 to 23 weeks of age and total RNA was extracted from the lung tumors. SurePrint G3 Mouse GE Microarray 8×60K Ver.2.0 were performed.
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