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

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 3

Intermetastatic differences in stromal cell dynamics during CRC metastasis.

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Intermetastatic differences in stromal cell dynamics during CRC metastas...
(A) Pathway enrichment analysis with published inflammatory signatures in myCAFs and iCAFs. (B) UMAP plot of myCAFs and iCAFs identified by joint application of RCA and CCA and color coded by cell subtype (upper panel). Proportions of cell subtypes in PT, LM, and PC tissue (lower panel) on average are shown. (C) Expression level of apCAF gene score (Supplemental Table 4) in CAFs from PT, LM, and PC depicted as violin plot. (D) Expression of the top 3 differentially expressed genes involved in antigen presentation in CAFs of PT, LM, and PC centered to the average expression of each gene across all locations. Dot size represents the proportion of expressing cells in each cluster. (E) Differential numbers of L-R interactions between CAFs and tumor cells in LM compared with PC. Green, upregulation in PC compared with LM; blue, downregulation in PC compared with LM. (F) Expression level of significantly upregulated exemplary L or R genes in PC compared with LM depicted as stacked violin plot. (G) Significantly upregulated L-R pairs between CAFs and tumor cells in PC compared with LM depicted as circle plot. (H) Pathway enrichment analysis in endothelial cells from LM and PC with published gene signatures. (I) Expression levels of significantly upregulated exemplary genes involved in inflammation and proliferation in PC and LM depicted as stacked violin plot. (J) Expression levels of antigen presentation and angiogenesis gene scores (Supplemental Table 4) in endothelial cells from LM and PC depicted as ridge plot. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, Student’s t test.