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Sortilin inhibition limits secretion-induced progranulin-dependent breast cancer progression and cancer stem cell expansion.

ABSTRACT: BACKGROUND:Cancer progression is influenced by genetic aberrations in the cancer cell population as well as by other factors including the microenvironment present within a tumour. Direct interactions between various cell types as well as cellular signalling via secreted cytokines can drive key tumourigenic properties associated with disease progression and treatment resistance. Also, cancer stem cell functions are influenced by the microenvironment. This challenging subset of cells has been linked to malignant properties. Within a screen, using in vivo like growth conditions, we identified progranulin as a highly secreted cytokine affecting cancer stem cells in breast cancer. This cytokine is known to play a role in numerous biological and tumour-related processes including therapy resistance in a range of cancer types. METHODS:Different in vitro and in vivo relevant conditions were used to validate breast cancer stem cell expansion mediated by progranulin and its receptor sortilin. Small interfering ribonucleic acid (siRNA) and pharmacological inhibition of sortilin were used to elucidate the role of sortilin as a functional receptor during progranulin-induced breast cancer stem cell propagation, both in vitro and in vivo, using breast cancer xenograft models. In addition, single-cell gene expression profiling as well as a Sox2 reporter breast cancer cell line were used to validate the role of dedifferentiation mediated by progranulin. RESULTS:In various in vivo-like screening assays, progranulin was identified as a potent cancer stem cell activator, highly secreted in ER?-negative breast cancer as well as in ER?-positive breast cancer under hypoxic adaptation. Progranulin exposure caused dedifferentiation as well as increased proliferation of the cancer stem cell pool, a process that was shown to be dependent on its receptor sortilin. Subcutaneous injections of progranulin or its active domain (GRN A) induced lung metastases in breast cancer xenograft models, supporting a major role for progranulin in cancer progression. Importantly, an orally bioavailable small molecule (AF38469) targeting sortilin, blocked GRN A-induced lung metastases and prevented cancer cell infiltration of the skin. CONCLUSION:The collective results suggest that sortilin targeting represents a potential novel breast cancer therapy approach inhibiting tumour progression driven by secretion and microenvironmental influences.

SUBMITTER: Rhost S

PROVIDER: S-EPMC6245804 | biostudies-other | 2018 Nov

REPOSITORIES: biostudies-other

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Sortilin inhibition limits secretion-induced progranulin-dependent breast cancer progression and cancer stem cell expansion.

Rhost Sara S Hughes Éamon É Harrison Hannah H Rafnsdottir Svanheidur S Jacobsson Hanna H Gregersson Pernilla P Magnusson Ylva Y Fitzpatrick Paul P Andersson Daniel D Berger Karoline K Ståhlberg Anders A Landberg Göran G

Breast cancer research : BCR 20181120 1

<h4>Background</h4>Cancer progression is influenced by genetic aberrations in the cancer cell population as well as by other factors including the microenvironment present within a tumour. Direct interactions between various cell types as well as cellular signalling via secreted cytokines can drive key tumourigenic properties associated with disease progression and treatment resistance. Also, cancer stem cell functions are influenced by the microenvironment. This challenging subset of cells has ...[more]

PMID: 30454027

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Project description:BackgroundThe growth factor progranulin has been implicated in numerous biological processes such as wound healing, inflammation and progressive tumorigenesis. Both progranulin and its receptor sortilin are known to be highly expressed in subgroups of breast cancer and have been associated with various clinical properties including tamoxifen resistance. Recent data further suggest that progranulin, via its receptor sortilin, drives breast cancer stem cell propagation in vitro and increases metastasis formation in an in vivo breast cancer xenograft model. In this retrospective biomarker analysis, we aimed to determine whether tumor co-expression of progranulin and sortilin has prognostic and treatment predictive values for breast cancer patients.MethodsWe explored how co-expression of progranulin and sortilin was associated with established clinical markers by analyzing a tissue microarray including 560 randomized premenopausal breast cancer patients receiving either 2 years of tamoxifen treatment or no adjuvant treatment, with a median follow-up time of 28 years. Breast cancer-specific survival was analyzed using Kaplan-Meier and Cox Proportional Hazards regression models to assess the prognostic and predictive value of progranulin and sortilin in relation to known clinical markers.ResultsCo-expression of progranulin and sortilin was observed in 20% of the breast cancer samples. In untreated patients, prognostic considerations could be detailed separately from treatment prediction and the high progranulin and sortilin expressing subgroup was significantly associated with breast cancer-specific death in multivariable analyses (HR=2.188, CI: 1.317-3.637, p=0.003) along with tumor size, high tumor grade and lymph node positivity. When comparing the untreated patients with tamoxifen treated patients in the ERα positive subgroup, co-expression of progranulin and sortilin was not linked to tamoxifen resistance.ConclusionData suggest that co-expression of progranulin and its receptor sortilin is a novel prognostic biomarker combination identifying a highly malignant subgroup of breast cancer. Importantly, this subpopulation could potentially be targeted with anti-sortilin based therapies.

Project description:Progranulin (PGRN), a widely secreted growth factor, is involved in multiple biological functions, and mutations located within the PGRN gene (GRN) are a major cause of frontotemporal lobar degeneration with TDP-43-positive inclusions (FLTD-TDP). In light of recent reports suggesting PGRN functions as a protective neurotrophic factor and that sortilin (SORT1) is a neuronal receptor for PGRN, we used a Sort1-deficient (Sort1-/-) murine primary hippocampal neuron model to investigate whether PGRN's neurotrophic effects are dependent on SORT1. We sought to elucidate this relationship to determine what role SORT1, as a regulator of PGRN levels, plays in modulating PGRN's neurotrophic effects.As the first group to evaluate the effect of PGRN loss in Grn knockout primary neuronal cultures, we show neurite outgrowth and branching are significantly decreased in Grn-/- neurons compared to wild-type (WT) neurons. More importantly, we also demonstrate that PGRN overexpression can rescue this phenotype. However, the recovery in outgrowth is not observed following treatment with recombinant PGRN harboring missense mutations p.C139R, p.P248L or p.R432C, indicating that these mutations adversely affect the neurotrophic properties of PGRN. In addition, we also present evidence that cleavage of full-length PGRN into granulin peptides is required for increased neuronal outgrowth, suggesting that the neurotrophic functions of PGRN are contained within certain granulins. To further characterize the mechanism by which PGRN impacts neuronal morphology, we assessed the involvement of SORT1. We demonstrate that PGRN induced-outgrowth occurs in the absence of SORT1 in Sort1-/- cultures.We demonstrate that loss of PGRN impairs proper neurite outgrowth and branching, and that exogenous PGRN alleviates this impairment. Furthermore, we determined that exogenous PGRN induces outgrowth independent of SORT1, suggesting another receptor(s) is involved in PGRN induced neuronal outgrowth.

Project description:Background and Objective: Matricellular proteins modulate the micro environment of tumors and are recognized to contribute to tumor cell invasion and dissemination. The cysteine-rich angiogenic inducer 61 (CYR61) is upregulated in mesenchymal transformed and invasive breast cancer cells. CYR61 correlates with poor prognosis of breast cancer patients. The signaling mechanism that causes invasive properties of cancer cells regarding to epithelial-mesenchymal transition (EMT) needs further research. In this study, we investigated the signaling mechanism, which is responsible for reduced cell invasion after suppression of CYR61 in mesenchymal transformed breast cancer cells and in triple negative breast cancer cells. Methods: We addressed this issue by generating a mesenchymal transformed breast cancer cell line using prolonged mammosphere cultivation. Western blotting and quantitative PCR were used to analyze gene expression alterations. Transient gene silencing was conducted using RNA interference. Proliferation was assessed using AlamarBlue assay. Invasiveness was analyzed using 2D and 3D invasion assays. Immune-histochemical analysis of patient tissue samples was performed to examine the prognostic value of CYR61 expression. Results: In this study, we investigated whether CYR61 could be used as therapeutic target and prognostic marker for invasive breast cancer. We discovered an interaction of CYR61 with metastasis-associated protein S100A4. Suppression of CYR61 by RNA interference reduced the expression of S100A4 dependent on ERK1/2 activity regulation. Non-invasive breast cancer cells became invasive due to extracellular CYR61 supplement. Immune-histochemical analysis of 239 patient tissue samples revealed a correlation of higher CYR61 and S100A4 expression with invasive breast cancer and metastasis. Conclusion: Our data suggest that suppression of CYR61 impedes the formation of an invasive cancer cell phenotype by reducing ERK1/2 phosphorylation thereby suppressing S100A4. These findings identify mechanisms by which CYR61 suppresses cell invasion and suggest it to be a potential therapeutic target and prognostic marker for invasive breast cancer and metastasis.

Dataset Information

Sortilin inhibition limits secretion-induced progranulin-dependent breast cancer progression and cancer stem cell expansion.

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Sortilin inhibition limits secretion-induced progranulin-dependent breast cancer progression and cancer stem cell expansion.

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