{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:06:03Z","timestamp":1776729963858,"version":"3.51.2"},"reference-count":0,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T00:00:00Z","timestamp":1773619200000},"content-version":"am","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>While lineage plasticity is a well-established driver of therapy resistance in prostate cancer, the role of tumor-infiltrating immune cells in mediating phenotype switching remains poorly understood. Here, we employed single-cell multi-omics to systematically characterize immune infiltration dynamics, transcriptional reprogramming, and intercellular communication networks during prostate cancer progression. Our analysis revealed that granulin (GRN)-expressing macrophages orchestrate the transition from adenocarcinoma (Adeno) to a therapy-resistant multilineage state exhibiting vimentin (VIM)+ mesenchymal and stem-like features through GRN\/ tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) interaction and the subsequent activation of the nuclear factor kappa-B (NF-\u03baB) pathway. Intriguingly, these plastic tumor subclones reciprocally enhanced GRN expression in macrophages via colony stimulating factor 1 (CSF1) and CSF1 receptor (CSF1R) receptor-ligand axis, establishing a feedforward signaling loop that sustains lineage plasticity. Functional validation demonstrated GRN\u2019s critical role in driving epithelial-mesenchymal transition in vitro and conferring resistance to enzalutamide (ENZ) in patient-derived organoids. Therapeutic intervention studies in transgenic Adeno of the mouse prostate (TRAMP) models showed that CSF1R inhibition disrupted this vicious cycle, reducing GRN \u00a0+ macrophages and suppressing multilineage subclone emergence. Spatial mapping revealed direct physical interactions between VIM \u00a0+ tumor cells and GRN \u00a0+ macrophages, while single-cell proteomics in castration-resistant patients confirmed the clinical relevance of this axis. Furthermore, we identified three novel stromal populations [decorin (DCN)+ endothelial cells, C-C motif chemokine ligand 7 (CCL7)+ fibroblasts, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT1)+ neutrophils associated with disease relapse. These findings illuminate the tumor-immune crosstalk underlying treatment resistance and unveil promising therapeutic targets for overcoming lineage plasticity-driven resistance in advanced prostate cancer.<\/jats:p>","DOI":"10.1093\/gpbjnl\/qzag024","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T04:35:57Z","timestamp":1773635757000},"source":"Crossref","is-referenced-by-count":1,"title":["Granulin+ Macrophages Promote Lineage Plasticity in Prostate Cancer Through Paracrine Signaling Loops"],"prefix":"10.1093","author":[{"given":"Zhipeng","family":"Zhu","sequence":"first","affiliation":[{"name":"Peking University Third Hospital Institute of Medical Innovation and Research, , Beijing 100191,","place":["China"]},{"name":"Peking University Third Hospital Cancer Center, , Beijing 100191,","place":["China"]},{"name":"Beijing Key Laboratory for Interdisciplinary Research in Gastrointestinal Oncology (BLGO) , Beijing 100191,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chinese PLA General Hospital College of Pulmonary and Critical Care Medicine, 8th Medical Center, , Beijing 100091,","place":["China"]},{"name":"Chinese PLA General Hospital Department of Pulmonary and Critical Care Medicine, 7th Medical Center, , Beijing 100091,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Song","sequence":"additional","affiliation":[{"name":"Peking University Third Hospital Institute of Medical Innovation and Research, , Beijing 100191,","place":["China"]},{"name":"Peking University Third Hospital Cancer Center, , Beijing 100191,","place":["China"]},{"name":"Beijing Key Laboratory for Interdisciplinary Research in Gastrointestinal Oncology (BLGO) , Beijing 100191,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Jiang","sequence":"additional","affiliation":[{"name":"Tongji University Department of Urology, Tongji Hospital, School of Medicine, , Shanghai 200065,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Cao","sequence":"additional","affiliation":[{"name":"Peking University Cancer Hospital & Institute Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, , Beijing 100091,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yicong","family":"Yao","sequence":"additional","affiliation":[{"name":"Tongji University Department of Urology, Tongji Hospital, School of Medicine, , Shanghai 200065,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaotong","family":"Yu","sequence":"additional","affiliation":[{"name":"Peking University Third Hospital Institute of Medical Innovation and Research, , Beijing 100191,","place":["China"]},{"name":"Peking University Third Hospital Cancer Center, , Beijing 100191,","place":["China"]},{"name":"Beijing Key Laboratory for Interdisciplinary Research in Gastrointestinal Oncology (BLGO) , Beijing 100191,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Peking University Third Hospital State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Center for Reproductive Medicine, , Beijing 100191,","place":["China"]},{"name":"Peking University Third Hospital National Clinical Research Center for Obstetrics and Gynecology, , Beijing 100191,","place":["China"]},{"name":"Key Laboratory of Assisted Reproduction (Peking University) , Ministry of Education, Beijing 100191,","place":["China"]},{"name":"Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology , Beijing 100191,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Husile","family":"Baiyin","sequence":"additional","affiliation":[{"name":"Peking University Third Hospital Institute of Medical Innovation and Research, , Beijing 100191,","place":["China"]},{"name":"Peking University Third Hospital Cancer Center, , Beijing 100191,","place":["China"]},{"name":"Beijing Key Laboratory for Interdisciplinary Research in Gastrointestinal Oncology (BLGO) , Beijing 100191,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"De","family":"Chang","sequence":"additional","affiliation":[{"name":"Chinese PLA General Hospital College of Pulmonary and Critical Care Medicine, 8th Medical Center, , Beijing 100091,","place":["China"]},{"name":"Chinese PLA General Hospital Department of Pulmonary and Critical Care Medicine, 7th Medical Center, , Beijing 100091,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denglong","family":"Wu","sequence":"additional","affiliation":[{"name":"Tongji University Department of Urology, Tongji Hospital, School of Medicine, , Shanghai 200065,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaolu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Peking University Third Hospital State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Center for Reproductive Medicine, , Beijing 100191,","place":["China"]},{"name":"Peking University Third Hospital National Clinical Research Center for Obstetrics and Gynecology, , Beijing 100191,","place":["China"]},{"name":"Key Laboratory of Assisted Reproduction (Peking University) , Ministry of Education, Beijing 100191,","place":["China"]},{"name":"Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology , Beijing 100191,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Wu","sequence":"additional","affiliation":[{"name":"Tongji University Department of Urology, Tongji Hospital, School of Medicine, , Shanghai 200065,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kailong","family":"Li","sequence":"additional","affiliation":[{"name":"Peking University Health Science Center Department of Biochemistry and Molecular Biology, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, School of Basic Medical Sciences, , Beijing 100191,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fengbiao","family":"Mao","sequence":"additional","affiliation":[{"name":"Peking University Third Hospital Institute of Medical Innovation and Research, , Beijing 100191,","place":["China"]},{"name":"Peking University Third Hospital Cancer Center, , Beijing 100191,","place":["China"]},{"name":"Beijing Key Laboratory for Interdisciplinary Research in Gastrointestinal Oncology (BLGO) , Beijing 100191,","place":["China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,3,15]]},"container-title":["Genomics, Proteomics &amp; 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