학술논문
An N-Cadherin 2 expressing epithelial cell subpopulation predicts response to surgery, chemotherapy and immunotherapy in bladder cancer.
Document Type
Academic Journal
Author
Gouin KH 3rd; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Ing N; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Plummer JT; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Rosser CJ; Department of Surgery (Urology), Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.; Ben Cheikh B; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Oh C; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Chen SS; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Chan KS; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Furuya H; Department of Surgery (Urology), Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.; Tourtellotte WG; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Knott SRV; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. simon.knott@cshs.org.; Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA. simon.knott@cshs.org.; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA. simon.knott@cshs.org.; Theodorescu D; Department of Surgery (Urology), Cedars-Sinai Medical Center, Los Angeles, CA, USA. dan.theodorescu@cshs.org.; Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA. dan.theodorescu@cshs.org.; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. dan.theodorescu@cshs.org.
Source
Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Subject
Language
English
Abstract
Neoadjuvant chemotherapy (NAC) prior to surgery and immune checkpoint therapy (ICT) have revolutionized bladder cancer management. However, stratification of patients that would benefit most from these modalities remains a major clinical challenge. Here, we combine single nuclei RNA sequencing with spatial transcriptomics and single-cell resolution spatial proteomic analysis of human bladder cancer to identify an epithelial subpopulation with therapeutic response prediction ability. These cells express Cadherin 12 (CDH12, N-Cadherin 2), catenins, and other epithelial markers. CDH12-enriched tumors define patients with poor outcome following surgery with or without NAC. In contrast, CDH12-enriched tumors exhibit superior response to ICT. In all settings, patient stratification by tumor CDH12 enrichment offers better prediction of outcome than currently established bladder cancer subtypes. Molecularly, the CDH12 population resembles an undifferentiated state with inherently aggressive biology including chemoresistance, likely mediated through progenitor-like gene expression and fibroblast activation. CDH12-enriched cells express PD-L1 and PD-L2 and co-localize with exhausted T-cells, possibly mediated through CD49a (ITGA1), providing one explanation for ICT efficacy in these tumors. Altogether, this study describes a cancer cell population with an intriguing diametric response to major bladder cancer therapeutics. Importantly, it also provides a compelling framework for designing biomarker-guided clinical trials.
(© 2021. The Author(s).)
(© 2021. The Author(s).)