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FOXA1 loss induces aggressive prostate cancer via unleashing basal/squamous de-differentiation and an immunosuppressive microenvironment [CosMx]

ABSTRACT: Forkhead box A1 (FOXA1) is a lineage-specifying transcription factor that is often de-regulated prostate cancer (PCa), with previous studies reporting both tumor-promoting and -inhibitory functions. Little is known about FOXA1 function in a physiological setting of PCa progression. Here we report that Foxa1 knockout in the Pten-null prostate epithelium in vivo leads to an aggressive sub-type of PCa marked by basal/squamous de-differentiation, tissue disorganization, and poor survival. Single-cell RNA-seq revealed a major increase of basal/squamous gene expression in the epithelium, which was accompanied by inflammatory and immunosuppressive cytokine signaling. Mechanistically, in addition to its well-known role in inducing luminal genes, FOXA1 directly inhibits many basal/squamous and inflammatory genes, which are unleashed upon Foxa1 knockout. Significantly, there is a striking remodeling of the tumor immune microenvironment in Foxa1-depleted PCa, with increased tumor infiltration by immunosuppressive myeloid populations and dysfunctional and spatially confined T cells. These important findings were further confirmed in human PCa samples via single-cell and spatial transcriptomic analyses. Altogether, we report critical roles for FOXA1 loss in inducing basal/squamous de-differentiation and an immunosuppressive microenvironment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282721 | GEO | 2026/02/21

REPOSITORIES: GEO

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Project description:Prostate cancer (PCa) remains the malignancy with the highest morbidity in men (1). Although early-stage PCa usually causes no symptoms, cancer cells in prostate glands readily metastasize to bones, lymph nodes, lungs, and liver during PCa progression (2). Common strategies, including surgery, radiation therapy, and androgen-deprivation therapy, are promising treatments for early-stage PCa. However, advanced PCa still lacks effective therapeutic strategies (3-5). Thus, researchers are currently focused on inhibiting tumor progression to explore effective therapeutic strategies for PCa treatment (6, 7). Cancer-associated fibroblasts (CAFs), stromal cells derived from normal fibroblasts or epithelia, are one of the major cellular components in the tumor microenvironment (8, 9). Compared with normal fibroblasts, CAFs are activated with increased expression of key protein markers, such as α-SMA, FAP, vimentin and S100A4 protein (10, 11). In the tumor microenvironment, CAFs secrete various growth effectors or cytokines to the extracellular matrix and thereby promote tumor progression by directly enhancing cancer cell growth, angiogenic induction, the extracellular matrix modification, and tumor-promoting inflammatory mediation (11-14). Notably, CAFs could act as an immunosuppressive mediator for the formation of an immunosuppressive tumor environment by recruiting and activating multiple immune cells (15). As such, CAFs might be a potential target in anti-tumor immunotherapy (16, 17). Currently, increased research has focused on inhibiting the immunosuppressive function of prostate cancer-associated fibroblasts (prostate CAFs), which may suggest therapeutic strategies for PCa (18, 19). Polysaccharides from Lentinus edodes are known to exhibit potent anti-tumor and immunomodulatory functions. The anti-tumor mechanisms of L. edodes polysaccharides include regulating the innate immune system by mediating CAF function, preventing tumorigenesis, or directly killing tumor cells via cell cycle regulation or apoptotic induction (20-22). Our previous studies isolated a novel polysaccharide component (MPSSS) from L. edodes. We found the secretome of prostate CAFs treated with MPSSS could inhibit the proliferation of CD4+ and CD8+ T cells, which suggested that MPSSS could prevent the immunosuppressive function of prostate CAFs (22). However, although the secretome of MPSSS-treated prostate CAFs inhibit the proliferation of T cells, how the secretome of MPSSS-treated prostate CAFs affect PCa progression is still unclear. The secretome defines as all proteins secreted by the organism or living cells into the extracellular space, which consists of soluble proteins and extracellular vesicles (EVs) (23). The secretome of prostate CAFs pays vital roles in PCa tumor origination, progression (24, 25). Since EVs contains various molecules (proteins, RNA, DNA and lipid) (26), we speculate that soluble proteins and EVs of prostate CAFs might have the different influence on PCa cells. In this study, the secretome of prostate CAFs untreated/treated with MPSSS were separated into the high molecular weight secretome (>100 kD) and the low molecular weight secretome (3-100 kD) using 100 kD and 3kD MWCO memberane filtration to narrow down the range of active components. The high molecular weight secretome contained extracellular vesicles (EVs) and large soluble proteins, while the low molecular weight secretome contained the small soluble proteins. The secretome of prostate CAFs untreated/treated with MPSSS were used to explore the underlying function and molecular mechanism using quantitative proteomics and multiple biochemical approaches.

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FOXA1 loss induces aggressive prostate cancer via unleashing basal/squamous de-differentiation and an immunosuppressive microenvironment [CosMx]

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