Single-cell deconvolution reveals high lineage- and location-dependent heterogeneity in mesenchymal multivisceral stage 4 colorectal cancer
Christopher Berlin, Bernhard Mauerer, Pierre Cauchy, Jost Luenstedt, Roman Sankowski, Lisa Marx, Reinhild Feuerstein, Luisa Schaefer, Florian R. Greten, Marina Pesic, Olaf Groß, Marco Prinz, Naomi Ruehl, Laura Miketiuk, Dominik Jauch, Claudia Laessle, Andreas Jud, Esther A. Biesel, Hannes Neeff, Stefan Fichtner-Feigl, Philipp A. Holzner, Rebecca Kesselring
Christopher Berlin, Bernhard Mauerer, Pierre Cauchy, Jost Luenstedt, Roman Sankowski, Lisa Marx, Reinhild Feuerstein, Luisa Schaefer, Florian R. Greten, Marina Pesic, Olaf Groß, Marco Prinz, Naomi Ruehl, Laura Miketiuk, Dominik Jauch, Claudia Laessle, Andreas Jud, Esther A. Biesel, Hannes Neeff, Stefan Fichtner-Feigl, Philipp A. Holzner, Rebecca Kesselring
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Research Article Cell biology Oncology

Single-cell deconvolution reveals high lineage- and location-dependent heterogeneity in mesenchymal multivisceral stage 4 colorectal cancer

Abstract

Metastasized colorectal cancer (CRC) is associated with a poor prognosis and rapid disease progression. Besides hepatic metastasis, peritoneal carcinomatosis is the major cause of death in Union for International Cancer Control (UICC) stage IV CRC patients. Insights into differential site-specific reconstitution of tumor cells and the corresponding tumor microenvironment are still missing. Here, we analyzed the transcriptome of single cells derived from murine multivisceral CRC and delineated the intermetastatic cellular heterogeneity regarding tumor epithelium, stroma, and immune cells. Interestingly, we found an intercellular site-specific network of cancer-associated fibroblasts and tumor epithelium during peritoneal metastasis as well as an autologous feed-forward loop in cancer stem cells. We furthermore deciphered a metastatic dysfunctional adaptive immunity by a loss of B cell–dependent antigen presentation and consecutive effector T cell exhaustion. Furthermore, we demonstrated major similarities of this murine metastatic CRC model with human disease and — based on the results of our analysis — provided an auspicious site-specific immunomodulatory treatment approach for stage IV CRC by intraperitoneal checkpoint inhibition.

Authors

Christopher Berlin, Bernhard Mauerer, Pierre Cauchy, Jost Luenstedt, Roman Sankowski, Lisa Marx, Reinhild Feuerstein, Luisa Schaefer, Florian R. Greten, Marina Pesic, Olaf Groß, Marco Prinz, Naomi Ruehl, Laura Miketiuk, Dominik Jauch, Claudia Laessle, Andreas Jud, Esther A. Biesel, Hannes Neeff, Stefan Fichtner-Feigl, Philipp A. Holzner, Rebecca Kesselring

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Figure 8

PC is associated with a mesenchymal phenotype in human and murine CRC.

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PC is associated with a mesenchymal phenotype in human and murine CRC. (...
(A and B) GSEA (Signal2Noize) with Hallmark EMT gene signature in murine and human PC. NES, normalized expression score. (C) Representative Western blot showing expression of depicted proteins in lysates from murine PT, LM, and PC. Fold change normalized to respective loading control (upper panel, β-actin; lower panel, HSP-90) and PT. The experiment was performed twice. (D) Western blot showing expression of depicted proteins in representative lysates from human PT, LM, and PC. Fold change normalized to respective loading control (upper panel, β-actin; lower panel, HSP-90) and PT. The experiment was performed twice. (E) Representative IHC of murine and human PT, LM, and PC for EPCAM, VIM, and ZEB1. IHC was performed on 10 tissue samples of each location. Scale bars: 100 μm.