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Single-cell deconvolution reveals high lineage- and location-dependent heterogeneity in mesenchymal multivisceral stage 4 colorectal cancer
Christopher Berlin, … , Philipp A. Holzner, Rebecca Kesselring
Christopher Berlin, … , Philipp A. Holzner, Rebecca Kesselring
Published December 28, 2023
Citation Information: J Clin Invest. 2024;134(5):e169576. https://doi.org/10.1172/JCI169576.
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Research Article Cell biology Oncology Article has an altmetric score of 2

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

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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 5

Impairment of B cell networks in metastasized CRC.

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Impairment of B cell networks in metastasized CRC.
(A) UMAP plot of 3,35...
(A) UMAP plot of 3,355 B cells identified by joint application of RCA and CCA and color coded by cell subtype (upper panel). Proportions of all cell subtypes in PT, LM, and PC (lower panel) on average are shown. Dashed lines mark primed and unprimed/immature B cell subtypes. (B) Ingoing and outgoing interaction strength of B cells with joint projection and clustering B cell subtypes onto shared 2D manifold according to their local descent. MET, combined analysis for LM and PC. Circle or square size is proportional to the signaling strength of respective cellular subtype. Different colors represent different B cell subtypes. (C) Unbiased overall information flow of signaling networks by summarizing all the communication probabilities in respective networks. All the significant signaling pathways were ranked based on their differences of overall information flow within the inferred networks between PT and MET. Brown, enriched in PT; purple, enriched in MET. (D) Significant L-R pairs of the MHC-II signaling network between B cell subtypes and Th1 Cd4+ T cells in PT and MET. Edge width represents MHC-II–dependent communication probability.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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