Single-cell analysis of treatment-resistant prostate cancer: Implications of cell state changes for cell surface antigen–targeted therapies Journal Article
| Authors: | Zaidi, S.; Park, J.; Chan, J. M.; Roudier, M. P.; Zhao, J. L.; Gopalan, A.; Wadosky, K. M.; Patel, R. A.; Sayar, E.; Karthaus, W. R.; Kates, D. H.; Chaudhary, O.; Xu, T.; Masilionis, I.; Mazutis, L.; Chaligné, R.; Obradovic, A.; Linkov, I.; Barlas, A.; Jungbluth, A. A.; Rekhtman, N.; Silber, J.; Manova-Todorova, K.; Watson, P. A.; True, L. D.; Morrissey, C.; Scher, H. I.; Rathkopf, D. E.; Morris, M. J.; Goodrich, D. W.; Choi, J.; Nelson, P. S.; Haffner, M. C.; Sawyers, C. L. |
| Article Title: | Single-cell analysis of treatment-resistant prostate cancer: Implications of cell state changes for cell surface antigen–targeted therapies |
| Abstract: | 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. Copyright © 2024 the Author(s). Published by PNAS. |
| Keywords: | immunohistochemistry; clinical article; controlled study; human tissue; protein expression; unclassified drug; genetics; histopathology; nonhuman; adenocarcinoma; ki 67 antigen; biological marker; mouse; animal; metabolism; animals; mice; animal tissue; gene expression; carcinoembryonic antigen; animal experiment; animal model; transcription factor; pathology; protein p53; tumor antigen; tumor marker; cancer resistance; cell heterogeneity; neuroendocrine tumor; prostate cancer; prostatic neoplasms; gene expression regulation; gene expression regulation, neoplastic; membrane antigen; immunology; prostate specific membrane antigen; antigens, neoplasm; myc protein; prostate tumor; prostate biopsy; protein p63; prostate adenocarcinoma; gene regulatory network; tissue microarray; drug therapy; transcription factor yap1; transcription factor sox2; antigens, surface; neuroendocrine carcinoma; carcinoma, neuroendocrine; cytokeratin 8; synaptophysin; castration resistant prostate cancer; cell surface; heterogeneity; molecularly targeted therapy; transcription factor ezh2; hepatocyte nuclear factor 3beta; single cell analysis; single-cell analysis; procedures; transcription factor mash1; humans; human; male; article; prostatic neoplasms, castration-resistant; immunofluorescence assay; neurogenic differentiation factor; biomarkers, tumor; lineage plasticity; single cell rna seq; tumor associated calcium signal transducer 2; cell states; trefoil factor 3; epithelial maligancies; delta like ligand 3 protein; homeobox protein nkx 3.1; insulinoma associated protein 1; pou class 2 homeobox 3 protein; steap family member 1 protein; steap family member 2 protein |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 121 |
| Issue: | 28 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2024-07-09 |
| Start Page: | e2322203121 |
| Language: | English |
| DOI: | 10.1073/pnas.2322203121 |
| PUBMED: | 38968122 |
| PROVIDER: | scopus |
| PMCID: | PMC11252802 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Charles L. Sawyers -- Source: Scopus |
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