An N-Cadherin 2 expressing epithelial cell subpopulation predicts response to surgery, chemotherapy and immunotherapy in bladder cancer

Kenneth H. Gouin, Nathan Ing, Jasmine T. Plummer, Charles J. Rosser, Bassem Cheikh, Catherine Oh, Stephanie S. Chen, Keith Syson Chan, Hideki Furuya, Warren G. Tourtellotte, Simon R. V. Knott () and Dan Theodorescu ()
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Kenneth H. Gouin: Cedars-Sinai Medical Center
Nathan Ing: Cedars-Sinai Medical Center
Jasmine T. Plummer: Cedars-Sinai Medical Center
Charles J. Rosser: Cedars-Sinai Medical Center
Bassem Cheikh: Cedars-Sinai Medical Center
Catherine Oh: Cedars-Sinai Medical Center
Stephanie S. Chen: Cedars-Sinai Medical Center
Keith Syson Chan: Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute
Hideki Furuya: Cedars-Sinai Medical Center
Warren G. Tourtellotte: Cedars-Sinai Medical Center
Simon R. V. Knott: Cedars-Sinai Medical Center
Dan Theodorescu: Cedars-Sinai Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25103-7

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