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

Abstract

BackgroundCancer 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.MethodsDifferent 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.ResultsIn various in vivo-like screening assays, progranulin was identified as a potent cancer stem cell activator, highly secreted in ERα-negative breast cancer as well as in ERα-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.ConclusionThe collective results suggest that sortilin targeting represents a potential novel breast cancer therapy approach inhibiting tumour progression driven by secretion and microenvironmental influences.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1060-5) contains supplementary material, which is available to authorized users.

Tumor Co-Expression of Progranulin and Sortilin Identifies a Highly Malignant Subgroup of Breast Cancer

“…Previous reports have associated high progranulin expression with ERα negative patients (16) as well as a predictive marker for recurrence in ERα positive breast cancer (29). We recently showed that progranulin secretion increased in ERα positive breast cancer when cells were subjected to hypoxia, whereas ERα negative breast cancer cells had constitutive high secretion of progranulin (7). Here we observed a signi cant link between progranulin and HIF1α, where tumors with high expression of HIF1α tend to express high progranulin.…”

“…Further, the progranulin receptor sortilin has been linked to breast cancer aggressiveness as well as being expressed in other types of cancer, such as prostate and ovarian cancer (31,36,37). Recent studies from our group have emphasized the stem cell propagating effect by progranulin through its receptor sortilin (7), indicating that this pathway could be central in mediating CSC properties during tumor progression. The existence of a targetable receptor further suggest that future cancer therapies could be developed, selectively targeting CSC propagation via sortilin.…”

“…The pleiotropic growth factor progranulin has been identi ed as a key mediator involved in breast cancer progression and is further in uenced by the tumor microenvironment, which can lead to breast CSC propagation and drug resistance (7)(8)(9)(10)(11)(12). We recently observed that progranulin secretion is induced from ERα positive breast cancer cells in hypoxic environment, which further induced breast CSC propagation (7).…”

“…The pleiotropic growth factor progranulin has been identi ed as a key mediator involved in breast cancer progression and is further in uenced by the tumor microenvironment, which can lead to breast CSC propagation and drug resistance (7)(8)(9)(10)(11)(12). We recently observed that progranulin secretion is induced from ERα positive breast cancer cells in hypoxic environment, which further induced breast CSC propagation (7). Progranulin is an autocrine growth factor involved in various biological processes, such as wound healing, tumorigenesis, in ammation, as well as various neurological diseases (13)(14)(15)(16)(17)(18)(19)(20).…”

The signal peptide as a new target for drug design

“…86,87 Progranulin has been identified as a secreted CSC modulator that contributes to breast cancer progression. 88 Progranulin's role in tumor growth and therapy-induced resistance in various cancer types is associated with its binding to the neuronal receptor sortilin. [89][90][91] Interest on the downmodulation of sortilin in breast cancer treatment is increasing as it is associated with breast cancer metastatic potential.…”