Sortilin targeted therapy in breast cancer with elevated progranulin expression
AffiliationInstitute of Biomedicine, Sahlgrenska Cancer Center, University of Gothenburg, Gothenburg
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AbstractBackground: A major challenge concerning breast cancer therapy is the occasional lack of effects using drugs that target cancer cells unspecifically. One possible explanation for this treatment failure is the existence of the small subpopulation of breast cancer stem cells that are believed to be more resistant towards conventional therapy and possesses the ability to drive tumor formation and disease progression. Cytokines secreted by nearby cells and other factors in the surrounding tumor microenvironment further stimulate the cancer cells, contributing to a heterogeneous and potentially more treatment resistant tumor. Thus, a more specific treatment approach targeting the breast cancer stem cell niche is crucial in preventing disease recurrences. In a cytokine screen, we identified progranulin as one of the main compounds secreted from cells exposed to hypoxia, leading to cancer stem cell propagation. Progranulin is involved in biological processes such as wound healing, inflammation and cancer progression. Progranulin and its receptor sortilin are known to be highly expressed in subgroups of breast cancer and are further associated with a clinically aggressive phenotype. Methods/Results: By carrying out a number of in vitro and in vivo like screening assays, we demonstrate that progranulin influences the stem cell population in breast cancer and is responsible for spreading a cancer stem cell promoting signal to normoxic tumor areas. In breast cancer, progranulin induces a dedifferentiation process in the receiving cancer cells and expression of cancer stem cell markers together with an EMT-associated gene expression profile, leading to cancer stem cell expansion. By using siRNA and pharmacological inhibition of sortilin, we show that sortilin is a functional receptor of progranulin and is responsible for driving progranulin induced breast cancer stem cell propagation. Supporting the role of progranulin in cancer progression, administration of progranulin in immunocompromised mice induce lung metastasis in our breast cancer xenograft models. The use of different approaches for blocking sortilin, such as sortilin inhibitors, down-modulators or sortilin-targeted antibodies can prevent this dedifferentiation process, both in vitro and in vivo, making the tumor cells less aggressive and metastatic. Conclusion: Targeting progranulin through its associated receptors is a potential therapeutic strategy for the treatment of patients with breast tumors having elevated progranulin or sortilin expression. By inhibiting the secretion based breast cancer progression, we could possibly block the formation of metastasis and cancer cell infiltration.
CitationBerger K, Rhost S, Hughes E, Harrison H, Rafnsdottir S, Jacobsson H, et al. Abstract P2-06-11: Sortilin targeted therapy in breast cancer with elevated progranulin expression. Cancer Res. 2019;79(4):P2-06-11-P2-06-11.
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