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Sortilin inhibition limits secretion-induced progranulin-dependent breast cancer progression and cancer stem cell expansion.
- Source :
-
Breast cancer research : BCR [Breast Cancer Res] 2018 Nov 20; Vol. 20 (1), pp. 137. Date of Electronic Publication: 2018 Nov 20. - Publication Year :
- 2018
-
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.<br />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.<br />Results: In 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.<br />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.
- Subjects :
- Adaptor Proteins, Vesicular Transport antagonists & inhibitors
Adaptor Proteins, Vesicular Transport genetics
Animals
Breast pathology
Cell Line, Tumor
Cell Transformation, Neoplastic
Disease Progression
Estrogen Receptor alpha metabolism
Female
Gene Expression Profiling
Humans
Hydrocarbons, Fluorinated pharmacology
Lung Neoplasms secondary
Mice
Mice, Inbred NOD
Mice, SCID
Progranulins administration & dosage
Pyridines pharmacology
RNA, Small Interfering metabolism
Single-Cell Analysis
Tissue Culture Techniques
Tumor Microenvironment
Xenograft Model Antitumor Assays
Adaptor Proteins, Vesicular Transport metabolism
Breast Neoplasms pathology
Lung Neoplasms pathology
Neoplastic Stem Cells pathology
Progranulins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1465-542X
- Volume :
- 20
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Breast cancer research : BCR
- Publication Type :
- Academic Journal
- Accession number :
- 30454027
- Full Text :
- https://doi.org/10.1186/s13058-018-1060-5