Integration Analysis of Single‐Cell Multi‐Omics Reveals Prostate Cancer Heterogeneity

Abstract

Prostate cancer (PCa) is an extensive heterogeneous disease with a complex cellular ecosystem in the tumor microenvironment (TME). However, the manner in which heterogeneity is shaped by tumors and stromal cells, or vice versa, remains poorly understood. In this study, single‐cell RNA sequencing, spatial transcriptomics, and bulk ATAC‐sequence are integrated from a series of patients with PCa and healthy controls. A stemness subset of club cells marked with SOX9highARlow expression is identified, which is markedly enriched after neoadjuvant androgen‐deprivation therapy (ADT). Furthermore, a subset of CD8+CXCR6+ T cells that function as effector T cells is markedly reduced in patients with malignant PCa. For spatial transcriptome analysis, machine learning and computational intelligence are comprehensively utilized to identify the cellular diversity of prostate cancer cells and cell‐cell communication in situ. Macrophage and neutrophil state transitions along the trajectory of cancer progression are also examined. Finally, the immunosuppressive microenvironment in advanced PCa is found to be associated with the infiltration of regulatory T cells (Tregs), potentially induced by an FAP+ fibroblast subset. In summary, the cellular heterogeneity is delineated in the stage‐specific PCa microenvironment at single‐cell resolution, uncovering their reciprocal crosstalk with disease progression, which can be helpful in promoting PCa diagnosis and therapy.

Immunosuppression in the prostate tumor microenvironment is tied to androgen deprivation therapy-resistant club-like cells

“…Our analysis also shows that the Club region is unperturbed by ADT, indicating that human club cells are similarly resistant to castration. High expression of transcription factors SOX9 , KLF5 , and ELF3 in the Club region is also indicative of the stem-like characteristics of these cells 72 .…”

“…Our analysis shows that the Club region is unperturbed by ADT, indicating that human club cells are similarly resistant to castration. Upregulated expression of transcription factors SOX9, KLF5, and ELF3 in the Club region is also indicative of the stem-like characteristics of these cells 71 . Whether these cells actively participate in the post-castration regeneration of the human prostate is beyond the scope of this study.…”

Cancer-associated fibroblasts and prostate cancer stem cells: crosstalk mechanisms and implications for disease progression

“…Specifically, preclinical and clinical trials have assessed the efficacy of targeting the Notch pathway {RO4929097 [( Stein et al, 2012 ) and PF-03084014 ( Du et al, 2018 ; Wang et al, 2020 )], [Hedgehog pathway (sonidegib ( Nanta et al, 2013 ), Gant-61 ( Rimkus et al, 2016 ), and GDC-0449 ( Tong et al, 2018 )], Wnt pathway (LGK974 ( Liu et al, 2013 ), OMP-54F28 ( Le et al, 2015 ), Foxy-5 ( Kelsey, 2017 ), and OMP-18R5 ( Gurney et al, 2012 )], and [ABC transporter protein pathways (cyclosporin A ( Kawahara et al, 2015 ), dofequidar fumarate ( Katayama et al, 2009 ), and vandetanib ( Horti et al, 2009 ; Azad et al, 2014 )]}. A recent study integrating single-cell RNA sequencing, spatial transcriptomics, and extensive ATAC sequencing identified a stemness subpopulation of cells labeled with SOX9highARlow expression that was significantly enriched after neoadjuvant ADT ( Bian et al, 2024 ). Under antiandrogenic stress, PCA cells may transiently dedifferentiate into stem-like cells via plasticity-related pathways and redifferentiate into therapeutically resistant and invasive CRPCs.…”