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.
Proceedings of the National Academy of Sciences of the United States of America. 2024 Jul 05 [Epub]
Samir Zaidi, Jooyoung Park, Joseph M Chan, Martine P Roudier, Jimmy L Zhao, Anuradha Gopalan, Kristine M Wadosky, Radhika A Patel, Erolcan Sayar, Wouter R Karthaus, D Henry Kates, Ojasvi Chaudhary, Tianhao Xu, Ignas Masilionis, Linas Mazutis, Ronan Chaligné, Aleksandar Obradovic, Irina Linkov, Afsar Barlas, Achim A Jungbluth, Natasha Rekhtman, Joachim Silber, Katia Manova-Todorova, Philip A Watson, Lawrence D True, Colm Morrissey, Howard I Scher, Dana E Rathkopf, Michael J Morris, David W Goodrich, Jungmin Choi, Peter S Nelson, Michael C Haffner, Charles L Sawyers
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Korea., Department of Urology, University of Washington, Seattle, WA 98195., Astrazeneca Oncology R&D, New York, NY 10016., Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263., Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA 98195., Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland., Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032., Molecular Cytology Core Facility, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York NY 10065., Research Outreach and Compliance, Memorial Sloan Kettering Cancer Center, New York, NY 10065., Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195., Department of Medicine, Division of Solid Tumor Oncology, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065.