Heterogeneity of cancer-associated fibroblast subpopulations in prostate cancer: Implications for prognosis and immunotherapy
Chen Ding, Jian‐Ge Wang, Jie Wang, Jiqiang Niu, Zhikai Xiahou, Zhou Sun, Zhenzhen Zhao, Dongyang Zeng
Abstract
• Heterogeneity of cancer-associated fibroblasts in prostate Cancer: this study characterizes four distinct CAF subpopulations (C0 IER2+, C1 ABCA8+, C2 ATI 3BP+, C3 MEOG 2+) within the prostate cancer tumor microenvironment. • Proliferative role of C1 ABCA8+ Fibroblasts: the C1 ABCA8+ subpopulation exhibits heightened proliferative activity, indicating its critical involvement in tumor growth and metastasis. • Impact of NFAT5 on prostate cancer Proliferation: in vitro experiments demonstrated that knockdown of the transcription factor NFAT5 in C1 ABCA8+ fibroblasts correlates with decreased cell proliferation in prostate cancer cell lines. • Prognostic model Development: a robust prognostic model was constructed based on gene expression profiles of CAF subpopulations, highlighting key genes associated with patient outcomes and immune landscape changes. • Targeting CAFs for enhanced Immunotherapy: the findings underscore the potential of targeting CAFs to improve immunotherapeutic strategies in prostate cancer, advocating for further research into CAF-specific therapies to enhance treatment efficacy. Prostate cancer stands as the second most common malignancy among men, notorious for its intricate heterogeneity, especially evident in metastatic disease. This complexity presents substantial challenges in treatment efficacy and patient prognosis. This study endeavors to elucidate the multifaceted roles of cancer-associated fibroblasts within the tumor microenvironment of prostate cancer, with a focus on their implications for disease prognosis and the potential for novel immunotherapeutic strategies. Leveraging advanced single-cell RNA sequencing technology, we meticulously characterized the diverse CAF subpopulations within prostate cancer samples. Our analysis identified four predominant subsets: C0 IER2 +, C1 ABCA8 +, C2 ABI3BP +, and C3 MEOX2 +. We conducted comprehensive gene expression profiling to construct a robust prognostic model reflecting the clinical relevance of these subpopulations. C1 ABCA8 + fibroblasts demonstrated heightened proliferative activity, underscoring their pivotal role in fostering tumor growth and metastasis via intricate signaling pathways. In vitro experiments verified that the T transcription factor NFAT5 of C1 ABCA8 + fibroblasts subpopulation was knocked down in LNCaP clone FGC and 22Rv1 cell lines, which was closely related to the proliferation of PC. Moreover, we identified key genes linked to patient outcomes and immune landscape alterations, reinforcing the prognostic significance of CAF characteristics in this context. This investigation illuminates the critical potential of targeting CAFs to augment immunotherapeutic approaches in prostate cancer. Our findings contribute to a deeper understanding of the TME's complexity, advocating for further exploration into CAF-targeted therapies aimed at enhancing treatment responses and ultimately improving patient outcomes. Heterogeneity of Fibroblasts in Prostate Cancer. Leveraging advanced single-cell RNA sequencing technology, we meticulously characterized the diverse CAF subpopulations within prostate cancer samples. C1 ABCA8 + Fibroblasts demonstrated heightened proliferative activity, underscoring their pivotal role in fostering tumor growth and metastasis via intricate signaling pathways. In vitro experiments verified that the TF NFAT5 of C1 ABCA8 + Fibroblasts subpopulation was knocked down in LNCaP clone FGC and 22Rv1 cell lines, which was closely related to the proliferation of PC. Moreover, we identified key genes linked to patient outcomes and immune landscape alterations, reinforcing the prognostic significance of CAF characteristics in this context.