WNT1-inducible signaling pathway protein 1 activation through C-X-C motif chemokine ligand 5/C-X-C chemokine receptor type 2/leukemia inhibitory factor/leukemia inhibitory factor receptor signaling promotes immunosuppression and neuroendocrine differentiation in prostate cancer
Ke Hung Tsui,
Chien-Liang Liu,
Hsiu-Lien Yeh,
Ming-Kun Liu,
Chien-Hsiu Li,
Wei-Hao Chen,
Kuo-Ching Jiang,
Han-Ru Li,
Phan Vu Thuy Dung,
Michael Hsiao,
Wassim Abou-Kheir,
Yen-Nien Liu
Affiliations
Ke Hung Tsui
Department of Urology, Shuang Ho Hospital, Taipei Medical University, Taipei 110, Taiwan; Department of Urology, School of Medicine, College of Medical, Taipei Medical University, Taipei 110, Taiwan
Chien-Liang Liu
Department of Surgery, Division of Urology, Chi Mei Medical Center, Tainan 710, Taiwan
Hsiu-Lien Yeh
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
Ming-Kun Liu
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
Chien-Hsiu Li
Department of Urology, Shuang Ho Hospital, Taipei Medical University, Taipei 110, Taiwan
Wei-Hao Chen
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
Kuo-Ching Jiang
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
Han-Ru Li
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
Phan Vu Thuy Dung
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
Michael Hsiao
Genomics Research Center, Academia Sinica, Taipei 115, Taiwan
Wassim Abou-Kheir
Department of Anatomy, Cell Biology and Physiological Sciences Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
Yen-Nien Liu
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; Corresponding author
Summary: The interaction between prostate cancer (PCa) cells and prostate stromal cells fosters an immunosuppressive tumor microenvironment (TME) that promotes tumor growth and immune evasion. However, the specific signaling pathways involved remain unclear. We identified a key mechanism involving the CXCL5/CXCR2 and LIF/LIFR pathways, which create a feedforward loop that enhances neuroendocrine differentiation (NED) in PCa cells and upregulates WNT1-inducible signaling pathway protein 1 (WISP1) in both cell types. WISP1 upregulation is essential for inducing immune checkpoints and immunosuppressive cytokines via LIF/LIFR signaling and STAT3 phosphorylation. This process leads to increased neuroendocrine markers, immune checkpoints, cell proliferation, and migration. Notably, WISP1 levels in patient sera correlate with PCa progression, suggesting its potential as a biomarker. Our findings elucidate the mechanisms by which reciprocal communication between PCa cells and stromal cells contributes to the formation of an immunosuppressive TME, driving the malignant progression of PCa and highlighting potential targets for therapeutic intervention.
