IL6/JAK/STAT3-mediated crosstalk between cancer associated fibroblasts and epithelial cells promotes lineage plasticity and prostate cancer progression.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE236042 | GEO | 2025/02/05
REPOSITORIES: GEO
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Project description:Prostate cancer is a heterogeneous disease with a slow progression and a highly variable clinical outcome. The tumor suppressor gene TP53 is frequently mutated in prostate cancer and predictive of an early metastatic dissemination and unfavorable patient outcome. The progression of solid tumors to metastatic cancer is often associated with increased cell plasticity, but the mechanism underlying TP53-loss induced disease aggressiveness is unknown. Here we show that Trp53 deficiency in Pten-null prostatic epithelial cells does not impact the early proliferation of Pten-null epithelial cells and prostatic intraepithelial neoplasia formation, nor growth arrest and senescence entry at later time. Moreover, we demonstrate that it induces epithelial cell plasticity by stimulating IL6 production in cancer-associated fibroblasts, that in turn enhances Jak/Stat signaling in epithelial cells and promotes metastatic dissemination. Thus, TP53 restrains prostate cancer progression by preventing a pro-tumorigenic crosstalk between PTEN-deficient prostatic epithelial cells and the tumor microenvironment.
2025-02-05 | GSE236041 | GEO
Project description:Prostate cancer is a heterogeneous disease with a slow progression and a highly variable clinical outcome. The tumor suppressor gene TP53 is frequently mutated in prostate cancer and predictive of an early metastatic dissemination and unfavorable patient outcome. The progression of solid tumors to metastatic cancer is often associated with increased cell plasticity, but the mechanism underlying TP53-loss induced disease aggressiveness is unknown. Here we show that Trp53 deficiency in Pten-null prostatic epithelial cells does not impact the early proliferation of Pten-null epithelial cells and prostatic intraepithelial neoplasia formation, nor growth arrest and senescence entry at later time. Moreover, we demonstrate that it induces epithelial cell plasticity by stimulating IL6 production in cancer-associated fibroblasts, that in turn enhances Jak/Stat signaling in epithelial cells and promotes metastatic dissemination. Thus, TP53 restrains prostate cancer progression by preventing a pro-tumorigenic crosstalk between PTEN-deficient prostatic epithelial cells and the tumor microenvironment.
2025-02-05 | GSE236040 | GEO
Project description:IL6/JAK/STAT3-mediated crosstalk between cancer associated fibroblasts and epithelial cells promotes lineage plasticity and prostate cancer progression.
| PRJNA988480 | ENA
Project description:IL6/JAK/STAT3-mediated crosstalk between cancer associated fibroblasts and epithelial cells promotes lineage plasticity and prostate cancer progression [scRNA-seq]
| PRJNA988485 | ENA
Project description:IL6/JAK/STAT3-mediated crosstalk between cancer associated fibroblasts and epithelial cells promotes lineage plasticity and prostate cancer progression [scATAC-seq]
| PRJNA988486 | ENA
Project description:Drug resistance in cancer is often linked to changes in tumor cell state or lineage, but the molecular mechanisms driving this plasticity remain unclear. Using murine organoid and genetically engineered mouse models, we investigated the causes of lineage plasticity in prostate cancer and its relationship to antiandrogen resistance. We found that plasticity initiates in an epithelial population defined by mixed luminal-basal phenotype and that it depends on increased Janus kinase (JAK) and fibroblast growth factor receptor (FGFR) activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce the dependency observed in mice by up-regulating luminal gene expression upon JAK and FGFR inhibitor treatment. Single-cell analysis confirms the presence of mixed-lineage cells with increased JAK/STAT (signal transducer and activator of transcription) and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials.
| S-EPMC9653178 | biostudies-literature
Project description:Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.
| S-EPMC6969104 | biostudies-literature
Project description:Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer, is characterized by loss of AR signaling and resulting resistance to AR-targeted therapy during neuroendocrine transdifferentiation, for which the molecular mechanisms remain unclear. Here, we report that neuropilin 2 (NRP2) is upregulated in both de novo and therapy-induced NEPC, which induces neuroendocrine markers, neuroendocrine cell morphology, and NEPC cell aggressive behavior. NRP2 silencing restricted NEPC tumor xenograft growth. Mechanistically, NRP2 engages in reciprocal crosstalk with AR, where NRP2 is transcriptionally inhibited by AR, and in turn suppresses AR signaling by downregulating the AR transcriptional program and confers resistance to enzalutamide. Moreover, NRP2 physically interacts with VEGFR2 through the intracellular SEA domain to activate STAT3 phosphorylation and subsequently SOX2, thus driving NEPC differentiation and growth. Collectively, these results characterize NRP2 as a driver of NEPC and suggest NRP2 as a potential therapeutic target in NEPC.
| S-EPMC9464715 | biostudies-literature
Project description:BackgroundThe gut microbiota is reportedly involved in the progression and chemoresistance of various human malignancies. However, the underlying mechanisms behind how it exerts some effect on prostate cancer, as an extra-intestinal tumor, in a contact-independent way remain elusive and deserve exploration. Antibiotic exposure, one of the various factors affecting the gut microbiota community and capable of causing gut dysbiosis, is associated with multiple disorders. This study aims to preliminarily clarify the link between gut dysbiosis and prostate cancer.ResultsFirst, we discovered that perturbing the gut microbiota by consuming broad-spectrum antibiotics in water promoted the growth of subcutaneous and orthotopic tumors in mice. Fecal microbiota transplantation could transmit the effect of antibiotic exposure on tumor growth. Then, 16S rRNA sequencing for mouse feces indicated that the relative abundance of Proteobacteria was significantly higher after antibiotic exposure. Meanwhile, intratumoral lipopolysaccharide (LPS) profoundly increased under the elevation of gut permeability. Both in vivo and in vitro experiments revealed that the NF-κB-IL6-STAT3 axis activated by intratumoral LPS facilitated prostate cancer proliferation and docetaxel chemoresistance. Finally, 16S rRNA sequencing of patients' fecal samples revealed that Proteobacteria was enriched in patients with metastatic prostate cancer and was positively correlated with plasma IL6 level, regional lymph node metastasis status, and distant metastasis status. The receiver operating characteristic (ROC) curves showed that the relative abundance of Proteobacteria had better performance than the prostate-specific antigen (PSA) level in predicting the probability of distant metastasis in prostate cancer (area under the ROC curve, 0.860; p < 0.001).ConclusionCollectively, this research demonstrated that gut dysbiosis, characterized by the enrichment of Proteobacteria due to antibiotic exposure, resulted in the elevation of gut permeability and intratumoral LPS, promoting the development of prostate cancer via the NF-κB-IL6-STAT3 axis in mice. Considering findings from human patients, Proteobacteria might act as an intestinal biomarker for progressive prostate cancer. Video Abstract.
| S-EPMC9202177 | biostudies-literature
Project description:We recently reported that restoring the CYP27A1-27hydroxycholesterol axis had antitumor properties. Thus, we sought to determine the mechanism by which 27HC exerts its anti-prostate cancer effects. As cholesterol is a major component of membrane microdomains known as lipid rafts, which localize receptors and facilitate cellular signaling, we hypothesized 27HC would impair lipid rafts, using the IL6-JAK-STAT3 axis as a model given its prominent role in prostate cancer. As revealed by single molecule imaging of DU145 prostate cancer cells, 27HC treatment significantly reduced detected cholesterol density on the plasma membranes. Further, 27HC treatment of constitutively active STAT3 DU145 prostate cancer cells reduced STAT3 activation and slowed tumor growth in vitro and in vivo. 27HC also blocked IL6-mediated STAT3 phosphorylation in nonconstitutively active STAT3 cells. Mechanistically, 27HC reduced STAT3 homodimerization, nuclear translocation, and decreased STAT3 DNA occupancy at target gene promoters. Combined treatment with 27HC and STAT3 targeting molecules had additive and synergistic effects on proliferation and migration, respectively. Hallmark IL6-JAK-STAT gene signatures positively correlated with CYP27A1 gene expression in a large set of human metastatic castrate-resistant prostate cancers and in an aggressive prostate cancer subtype. This suggests STAT3 activation may be a resistance mechanism for aggressive prostate cancers that retain CYP27A1 expression. In summary, our study establishes a key mechanism by which 27HC inhibits prostate cancer by disrupting lipid rafts and blocking STAT3 activation. IMPLICATIONS: Collectively, these data show that modulation of intracellular cholesterol by 27HC can inhibit IL6-JAK-STAT signaling and may synergize with STAT3-targeted compounds.
| S-EPMC7971119 | biostudies-literature