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Tumor cell-derived CTSZ mediates macrophage recruitment and M2 polarization to promote castration-resistant prostate cancer progression through the TRA2A/IL-32/ITGA5 axis

ABSTRACT: Castration-resistant prostate cancer (CRPC) is a lethal stage of prostate cancer after androgen deprivation therapy (ADT). However, most studies have focused on the autonomous alterations of CRPC cells, and the specific contribution of CRPC cells to the metastatic microenvironment remains less well understood. Here, we report that cathepsin Z (CTSZ) was overexpressed in CRPC cells, enhancing macrophage infiltration and promoting M2 polarization, ultimately leading to the metastasis of CRPC. Mechanistically, CTSZ facilitates the maturation of IL-32 mRNA by directly degrading the alternative splicing factor TRA2A in CRPC cells, thereby increasing the secretion of IL-32. Subsequently, elevated IL-32 directly binds to ITGA5 in macrophages and activates the PI3K/AKT/mTOR pathway in macrophages, thus promoting the recruitment and polarization of macrophages. Furthermore, treatment with an ITGA5 inhibitor blocked the effect of CTSZ overexpression and suppressed CRPC development. These findings uncover a novel mechanism wherein CTSZ involvement in cell‒cell interactions within the tumor microenvironment contributes to the progression of CRPC and provide new therapeutic strategies for CRPC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE246971 | GEO | 2023/11/20

REPOSITORIES: GEO

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Project description:Following treatment with androgen receptor (AR) pathway inhibitors, ~20% of prostate cancer patients progress by shedding their dependence on AR. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). Currently, no targeted therapies are available for CRPC-NEPCs. A major hurdle in the development of new therapies and treatment of CRPC-NEPC is the lack of accurate models to test candidate treatments. Such models would ideally capture components of the tumor microenvironment (TME) factors, which likely regulate the phenotypic, genetic, and epigenetic underpinnings of this aggressive subset. The TME is a complex system comprised not only of malignant prostate cells but also stromal and inflammatory cells and a scaffold of extracellular matrix (ECM). ECM proteins are implicated in the survival and progression of cancer and development of chemoresistance, while are equally integral to the development of prostate cancer organoids. Here, using a combination of patient tumor proteomics and RNA sequencing, we define putative ECM cues that may guide the growth of prostate tumors in patients. Using this molecular information, we developed synthetic hydrogels that recapitulate the tumor ECM. Organoids cultured in the synthetic hydrogel niches demonstrate that ECM subtypes regulate the morphology, transcriptome, and epigenetics hallmarks of CRPC-Adeno and CRPC-NEPC. CRPC-NEPC organoid showed a differential response to small molecule inhibitors of epigenetic repressor EZH2 and Dopamine Receptor D2 (DRD2), the latter being a novel target in CRPC-NEPC when grown in tumor-specific ECM. Finally, in those synthetic ECM niches where drug resistance was observed in CRPC-NEPCs, cellular reprogramming by a synergistic combination of EZH2 inhibitors with DRD2 antagonists inhibited tumor growth. The synthetic platform can provide a more realistic prostate-specific microenvironment and subsequently enable the development of effective targeted therapeutics for prostate cancers.

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Tumor cell-derived CTSZ mediates macrophage recruitment and M2 polarization to promote castration-resistant prostate cancer progression through the TRA2A/IL-32/ITGA5 axis

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