Abstract
Prostate cancer represents the major cause of cancer-related death in men and patients frequently develop drug-resistance and metastatic disease. Most studies focus on hormone-resistance mechanisms related to androgen receptor mutations or to the acquired property of prostate cancer cells to over-activate signaling pathways. Tumor microenvironment plays a critical role in prostate cancer progression. However, the mechanism involving androgen/androgen receptor signaling in cancer associated fibroblasts and consequences for prostate cancer progression still remains elusive. We now report that prostate cancer associated fibroblasts express a transcriptional-incompetent androgen receptor. Upon androgen challenging, the receptor co-localizes with the scaffold protein filamin A in the extra-nuclear compartment of fibroblasts, thus mediating their migration and invasiveness. Cancer-associated fibroblasts move towards epithelial prostate cancer cells in 2D and 3D cultures, thereby inducing an increase of the prostate cancer organoid size. Androgen enhances both these effects through androgen receptor/filamin A complex assembly in cancer-associated fibroblasts. An androgen receptor-derived stapled peptide, which disrupts the androgen receptor/filamin A complex assembly, abolishes the androgen-dependent migration and invasiveness of cancer associated fibroblasts. Notably, the peptide impairs the androgen-induced invasiveness of CAFs in 2D models and reduces the overall tumor area in androgen-treated 3D co-culture. The androgen receptor in association with β1 integrin and membrane type-matrix metalloproteinase 1 activates a protease cascade triggering extracellular matrix remodeling. The peptide also impairs the androgen activation of this cascade. This study offers a potential new marker, the androgen receptor/filamin A complex, and a new therapeutic approach targeting intracellular pathways activated by the androgen/androgen receptor axis in prostate cancer-associated fibroblasts. Such a strategy, alone or in combination with conventional therapies, may allow a more efficient treatment of prostate cancer.
Highlights
Prostate cancer (PC) represents the most common cancer in men over the age of 50 and skills currently available for its treatment include active surveillance, beam therapy, radical prostatectomy and pharmacologicOfficial journal of the Cell Death Differentiation AssociationDi Donato et al Cell Death and Disease (2021)12:127Tumor microenvironment is made up of a variety of stromal and inflammatory cells
cancerassociated fibroblasts (CAFs), but not human normal fibroblasts (HNFs), expressed α-smooth muscle actin (α-SMA) and fibroblast activation protein (FAP) (Fig. 1S, b), which are indicative of the fibroblast activated-phenotype[35]
In apparent contrast with these latter findings, a relationship between poor PC outcome and loss of stromal androgen receptor (AR) has been reported[13,36,58]. This discrepancy might be related to the loss of stromal AR occurring during CAF selection or degradation of the receptor by ubiquitin-proteasome pathways[38] or epigenetic modifications that destabilize the receptor protein[59]
Summary
Prostate cancer (PC) represents the most common cancer in men over the age of 50 and skills currently available for its treatment include active surveillance, beam therapy, radical prostatectomy and pharmacologicOfficial journal of the Cell Death Differentiation AssociationDi Donato et al Cell Death and Disease (2021)12:127Tumor microenvironment is made up of a variety of stromal and inflammatory cells. Once ‘activated’, CAFs reorganize the structure and composition of the connective tissue by depositing extracellular matrix (ECM) and releasing cytokines, as well as growth factors that remodel ECM, increase tumor stiffness and induce growth, invasiveness and drug-resistance of transformed epithelial cells[4]. Prostate CAFs enhance the gland transformation and promote PC progression[5,6,7] They constitute a ‘niche’ that sustains the function of cancer stem cells (CSCs), promoting metabolic re-programming of PC cells or their epithelial–mesenchyme transition Stromal AR induces prostatic intraepithelial neoplasia (PIN) or metastatic events[16,17]. Thereafter, the stromal receptor might induce changes in the tumor microenvironment composition and stimulate the release of growth factors, enabling metastatic events[19]
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