A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance

Al‐Akhrass, Hussein; Conway, James R. W.; Poulsen, Annemarie Svane Aavild; Paatero, Ilkka; Kaivola, Jasmin; Padzik, Artur; Andersen, Olav M.; Ivaska, Johanna

doi:10.1038/s41388-020-01604-5

Cited by 23 publications

(27 citation statements)

References 65 publications

(56 reference statements)

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“…According to Pietilä et al (2019) , the depletion of SORL1 triggers HER2 accumulation in dysfunctional lysosomes, and SORL1 -silenced cells showed antiproliferative effects on not only breast cancer but also bladder cancer by regulating oncogenic receptor tyrosine kinase (RTK) signaling. This group further investigated the role of SORL1 in mediating targeted therapy resistance in breast cancer and discovered that SORL1 is necessary for HER2-HER3-driven oncogenic cell growth ( Al-Akhrass et al, 2021 ). However, Michael et al (2019) discovered that the downregulation of SORL1 expression facilitates tumor growth in a transplant tumor model and relatively low expression predicts a worse prognosis in human breast, lung, and gastric cancer patients.…”

Section: Discussionmentioning

confidence: 99%

Identification and Mechanism of the PD-1/PD-L1 Genomic Signature SORL1 as Protective Factor in Bladder Cancer

Chen

Shen

et al. 2021

Front. Genet.

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Background: Immunotherapy has recently shown remarkable efficacy for advanced bladder cancer patients. Accordingly, identifying a biomarker associated with the programmed cell death protein 1 (PD-1)/its ligand (PD-L1) genomic signature to predict patient prognosis is necessary.Methods: In this study, we used mutation data and RNA-seq data of bladder cancer samples acquired from The Cancer Genome Atlas (TCGA) database to combine PD-1/PD-L1-associated mutational signatures with PD-1/PD-L1-associated differentially expressed genes (DEGs). Then, we performed a Kaplan-Meier analysis on the corresponding clinical data of the TCGA bladder urothelial carcinoma (BLCA) cohort to identify prognostic genes, and the results were validated using the GSE48075 cohort. The online platform UCSC Xena was used to analyze the relationship between the candidate genes and clinical parameters. We utilized the Human Protein Atlas (HPA) database to validate the protein expression levels. Then, correlation analysis, cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) analysis, and gene set enrichment analysis (GSEA) were used to clarify the mechanism.Results: We identified one prognostic gene, sortilin related receptor 1 (SORL1), whose downregulation was associated with a comparatively advanced BLCA stage. While further exploring this finding, we found that SORL1 expression was negatively correlated with PD-1/PD-L1 expression and M2 macrophage levels. Furthermore, we found that the downregulation of SORL1 expression was significantly associated with a higher epithelial-mesenchymal transition (EMT) score.Conclusion: We described a novel PD-1/PD-L1-associated signature, SORL1, that predicts favorable outcomes in bladder cancer. SORL1 might reduce immune suppression and inhibit the M2 macrophage-induced EMT phenotype of tumor cells.

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Section: Discussionmentioning

confidence: 99%

Identification and Mechanism of the PD-1/PD-L1 Genomic Signature SORL1 as Protective Factor in Bladder Cancer

Chen

Shen

et al. 2021

Front. Genet.

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“…Some studies have shown that SORLA, through interactions at its extracellular domain, exists in a complex with HER2 and co-tra cs with HER2, facilitating HER2 recycling to the plasma membrane to support HER2 downstream signalling. In the absence of SORLA, HER2 becomes localized to enlarged, partially dysfunctional lysosomes, resulting in defective HER2 signalling and increased sensitivity [16,17]. Increasing evidence indicating the important roles that Sortilin and SorLA participate in a variety of tumour progression-related processes.…”

Section: Discussionmentioning

confidence: 99%

SorCS3 Promotes the Internalization of p75NTR to Inhibit Glioma Progression

Zhang

Fan

et al. 2021

Preprint

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Background: Glioma is a fatal malignancy caused by dysregulation of cellular signal transduction. Internalization plays a key role in maintaining signalling balance. SorCS3 is involved in nerve cell receptor internalization. However, the impact of SorCS3 on the biological processes involved in glioma has not yet been reported. Here, we highlight the potential of SorCS3-mediated regulation of signalling receptor internalization as a rational target for therapeutic intervention in glioma.Methods: SorCS3 expression was analysed in the TCGA and CGGA databases and in tissue microarrays. The effects of SorCS3 on the proliferation and metastasis of glioma cells were examined in vitro and in vivo with Transwell, wound healing, EdU incorporation and nude mouse tumorigenicity assays. Fluorescent 5-FAM, SE-labelled proteins were used to detect the internalization of SorCS3 in glioma cells. Immunofluorescence and Co-IP assays were conducted to investigate the downstream effector of SorCS3. Moreover, Dynasore and Ro 08-2750, inhibitors of internalization and NGF binding to p75NTR, respectively, were used to validate the biological functions of SorCS3 in glioma.Results: Our data demonstrated that SorCS3 was downregulated in glioma tissues and closely related to favourable prognosis. Overexpression of SorCS3 inhibited the proliferation and metastasis of glioma cells in vitro and in vivo, while silencing of SorCS3 exerted the opposite effects. Mechanistic investigations showed that SorCS3 bound to p75NTR, which subsequently increased the internalization of p75NTR, and then transported p75NTR to the lysosome for degradation, ultimately contributing to inhibition of glioma progression.Conclusions: Our work suggests that SorSC3 is a marker of promising prognosis in glioma patients and suggests that SorCS3 regulates internalization, which plays an important role in inhibiting glioma progression.

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“…Some of the methods employed in this study are the same as those described in our earlier publications [ 18 , 19 ]…”

Section: Methodsmentioning

confidence: 99%

“…The mature SorLA protein resides mainly in the trans‐Golgi network and undergoes constitutive antero‐ and retrograde trafficking to the plasma membrane through endosomes. Due to its central role in protein trafficking, SorLA has been implicated in the development and/or progression of neurological and metabolic diseases and most recently in cancer [ 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…Our previous studies unraveled a HER2 therapy resistance mechanism in which SorLA supports HER2 protein levels and oncogenicity in breast and bladder cancer in vitro and in vivo [ 16 ]. In addition, we have demonstrated that SorLA promotes HER2‐HER3 endosomal recycling to sustain their oncogenic signaling in vitro as well as in an anti‐HER2 therapy insensitive brain xenograft in vivo model [ 19 ]. The present study outlines the translational extension of our previous findings and aims to assess the druggability of SorLA in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

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Sortilin‐related receptor is a druggable therapeutic target in breast cancer

et al. 2021

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In breast cancer, the currently approved anti-receptor tyrosine-protein kinase erbB-2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative HER2-related therapeutic targets could offer a means to overcome these resistance mechanisms. We have previously demonstrated that an endosomal sorting protein, sortilin-related receptor (SorLA), regulates the traffic and signaling of HER2 and HER3, thus promoting resistance to HER2-targeted therapy in breast cancer. This study aims to assess the feasibility of targeting SorLA using a monoclonal antibody. Our results demonstrate that anti-SorLA antibody (SorLA ab) alters the resistance of breast cancer cells to HER2 monoclonal antibody trastuzumab in vitro and in ovo. We found that SorLA ab and trastuzumab combination therapy also inhibits tumor cell proliferation and tumor cell density in a mouse xenograft model of HER2-positive breast cancer. In addition, SorLA ab inhibits the proliferation of breast cancer patient-derived explant three-dimensional cultures. These results provide, for the first time, proof of principle that SorLA is a druggable target in breast cancer.

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A feed-forward loop between SorLA and HER3 determines heregulin response and neratinib resistance

Cited by 23 publications

References 65 publications

Identification and Mechanism of the PD-1/PD-L1 Genomic Signature SORL1 as Protective Factor in Bladder Cancer

Identification and Mechanism of the PD-1/PD-L1 Genomic Signature SORL1 as Protective Factor in Bladder Cancer

SorCS3 Promotes the Internalization of p75NTR to Inhibit Glioma Progression

Sortilin‐related receptor is a druggable therapeutic target in breast cancer

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