Cancer-Associated Fibroblasts Shape the Formation of Budding Cancer Cells at the Invasive Front of Human Colon Cancer

The formation of budding cancer cells at the invasive front of solid tumors is one of the first steps of metastasis. However, this process is still incompletely elucidated. Here, we used spatial molecular imaging to disentangle the complex interactions between cancer cells and the tumor microenvironment at the invasive front of colon tumors. Employing a 1,000-plex gene panel, we defined all major cell types in tumors and adjacent normal tissue with accurate spatial localization. Individual cancer cell clusters were mainly located together, consistent with an expected mutation- and epigenetic-driven clonal evolution. However, cancer cell clusters encompassing budding cells exhibited a markedly different spatial distribution. These cells were scattered around the periphery of the main cancer cell masses and were more frequently in contact with cancer-associated fibroblasts (CAFs). Our findings collectively suggest that CAFs induce pro-invasive gene expression changes involved in epithelial-mesenchymal transition, extracellular matrix binding, and migration.

Note:
Funding Information: This work was supported by the Lundbeck Foundation (R307-2018-3433), Riisfort Fonden, Novo Nordisk Foundation (Open Discovery Innovation Network (ODIN) program, grant NNF20SA0061466), the Danish Cancer Society (R304-A17698) (L.S.K.), and Købmand i Odense Johann og Hanne Weimann Født Seedorffs Legat (J.L.G.-R.).

Declaration of Interests: The authors declare no competing interests.

Ethical Approval Statement: he requirement for patient consent to the specific analyses was waived and The Danish National Committee on Health Research Ethics approved the study (approval number 2016120).

Keywords: Single Cell Analyses, CosMx Spatial Molecular Imager, Budding Cells, Epithelial-Mesenchymal Transition, Metastasis, Colon Cancer, Spatial Transcriptomics, Tumor Microenvironment, Cancer Associated Fibroblasts

Suggested Citation: Suggested Citation

García-Rodríguez, Juan Luis and Korsgaard, Ulrik and Vissing, Stine M. and Paasch, Thea Petersen and Jensby, Eva F. and Williams, Hannah L. and Salachan, Paul Vinu and Brandt, Camilla Blunk and Hanimann, Jacob and Lin, Lin and Zlobec, Inti and Sørensen, Karina D. and Kjems, Jørgen and Hager, Hendrik and Kristensen, Lasse and Administrator, Sneak Peek, Cancer-Associated Fibroblasts Shape the Formation of Budding Cancer Cells at the Invasive Front of Human Colon Cancer. Available at SSRN: https://ssrn.com/abstract=4935048 or http://dx.doi.org/10.2139/ssrn.4935048

This version of the paper has not been formally peer reviewed.