Single‐Cell Dissection of Therapy‐Induced Remodeling Uncovers a Fibroblast‐Driven Immunosuppressive Niche and Targetable Vulnerabilities in Lethal Prostate Cancer
Source abstract
Abstract
ABSTRACT Therapy resistance in prostate cancer arises from coordinated remodeling of malignant and stromal compartments, yet the mechanisms orchestrating this ecosystem adaptation remain elusive. Here, single‐cell RNA sequencing of longitudinal biopsies obtained before and after androgen‐deprivation therapy (ADT) delineated a therapy‐induced stromal lineage bifurcation toward APOD + and DPT + fibroblast states. DPT + fibroblasts activated a C3‐ITGAX/ITGB2 complement signaling axis targeting macrophages, coinciding with suppression of M1 inflammatory programs, amplification of immune‐checkpoint signaling, and a shift of CD8 + T cells from cytotoxic to exhausted phenotypes. Concomitantly, we identified pre‐existing malignant epithelial subpopulations characterized by reduced AR/KLK3 activity and heightened chromosomal instability that preferentially persisted following therapy. Integrative multi‐omic analyses nominated TSPAN1 as a functional effector of castrate resistant prostate cancer (CRPC) and NRXN1 as a regulator of neuroendocrine plasticity through calcium‐dependent signaling programs. Genetic silencing of either gene suppressed proliferation, clonogenicity, migration, and tumor growth, while attenuating neuroendocrine features in vitro and in vivo. Spatial mapping, functional perturbation, and stromal‐epithelial co‐culture experiments mechanistically established a therapy‐induced DPT + fibroblast‐complement circuit that enforced immune evasion and channels epithelial trajectories toward CRPC or neuroendocrine prostate cancer. Collectively, these findings defined the DPT + ‐complement‐macrophage axis as an actionable vulnerability and position TSPAN1 and NRXN1 as therapeutic entry points to disrupt ADT‐driven tumor ecosystem remodeling in prostate cancer.
Source: crossref · Quality: baseline
Research context
OpenAlex topics: Prostate Cancer Treatment and Research · Single-cell and spatial transcriptomics · Cancer Immunotherapy and Biomarkers
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
Affiliations
Department of Urology The First Affiliated Hospital of Guangxi Medical University Nanning Guangxi China
Center For Genomic and Personalized Medicine Guangxi Key Laboratory for Genomic and Personalized Medicine University Engineering Research Center of Digital Medicine and Healthcare, School of Life Science Guangxi Medical University Nanning Guangxi China
Institute of Urology and Nephrology First Affiliated Hospital of Guangxi Medical University Guangxi Medical University Nanning Guangxi China
Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education & Department of Biochemistry and Molecular Biology School of Basic Medical Sciences and Fudan University Shanghai Cancer Center Shanghai Medical College of Fudan University Shanghai China
State Key Laboratory of Common Mechanism Research for Major Diseases Suzhou Institute of Systems Medicine Chinese Academy of Medical Sciences & Peking Union Medical College Suzhou Jiangsu China
Disease Networks Research Unit Biocenter Oulu Faculty of Biochemistry and Molecular Medicine University of Oulu Oulu Finland
Key Laboratory of Longevity and Aging‐Related Disease of Chinese Ministry of Education Center for Translational Medicine, School of Basic Medical Sciences Guangxi Medical University Nanning Guangxi China
Cancer Institute Fudan University Shanghai Cancer Center Department of Oncology Shanghai Medical College of Fudan University Shanghai China
Funding
National Natural Science Foundation of China · Natural Science Foundation of Guangxi Province
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