Single- cell analysis of treatment- resistant prostate cancer: Implications of cell state changes for cell surface antigen- targeted therapies

• 成果类型: Article
• 署名作者: Zaidi, Samir; Park, Jooyoung; Chan, Joseph M.; Roudier, Martine P.; Zhao, Jimmy L.; Gopalan, Anuradha; Wadosky, Kristine M.; Patel, Radhika A.; Sayar, Erolcan; Karthaus, Wouter R.; Kates, D. Henry; Chaudhary, Ojasvi; Xu, Tianhao; Masilionis, Ignas; Mazutis, Linas; Chaligne, Ronan; Obradovic, Aleksandar; Linkov, Irina; Barlas, Afsar; Jungbluth, Achim A.; Rekhtman, Natasha; Silber, Joachim; Manova-Todorova, Katia; Watson, Philip A.; True, Lawrence D.; Morrissey, Colm; Scher, Howard I.; Rathkopf, Dana E.; Morris, Michael J.; Goodrich, David W.; Choi, Jungmin; Nelson, Peter S.; Haffner, Michael C.; Sawyers, Charles L.
• 署名单位: Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Korea University; Korea University Medicine (KU Medicine); Memorial Sloan Kettering Cancer Center; University of Washington; University of Washington Seattle; Memorial Sloan Kettering Cancer Center; Roswell Park Comprehensive Cancer Center; Fred Hutchinson Cancer Center; Fred Hutchinson Cancer Center; Swiss Federal Institutes of Technology Domain; Ecole Polytechnique Federale de Lausanne; Swiss School of Public Health (SSPH+); Swiss Institute Experimental Cancer Research; NewYork-Presbyterian Hospital; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; University of Washington; University of Washington Seattle; Yale University; Memorial Sloan Kettering Cancer Center; Howard Hughes Medical Institute
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9768
• DOI: 10.1073/pnas.2322203121
• 发表日期: 2024-07-09
• 关键词: lineage plasticity; ascl1; progression; activation; EVOLUTION; subtypes; neurod1

摘要

Targeting cell surface molecules using radioligand and antibody- based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)-a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single- cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate- resistant PRAD and NEPC than previously anticipated but also found that the expression of molecules targeted therapeutically, namely PSMA , STEAP1 , STEAP2 , TROP2, CEACAM5 , and DLL3 , varied within a subset of gene- regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to current and future antigen- directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.