Research Papers:

Macrophages induce “budding” in aggressive human colon cancer subtypes by protease-mediated disruption of tight junctions

Kari Trumpi, Nicola Frenkel, Timo Peters, Nicoline M. Korthagen, Jennifer M.J. Jongen, Daniëlle Raats, Helma van Grevenstein, Yara Backes, Leon M. Moons, Miangela M. Lacle, Jan Koster, Danny Zwijnenburg, Inne H.M. Borel Rinkes and Onno Kranenburg _

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Oncotarget. 2018; 9:19490-19507. https://doi.org/10.18632/oncotarget.24626

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Kari Trumpi1,*, Nicola Frenkel1,*, Timo Peters1, Nicoline M. Korthagen2,3, Jennifer M.J. Jongen1, Daniëlle Raats1, Helma van Grevenstein1, Yara Backes4, Leon M. Moons4, Miangela M. Lacle5, Jan Koster6, Danny Zwijnenburg6, Inne H.M. Borel Rinkes1 and Onno Kranenburg1

1UMC Utrecht Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands

2Orthopedics, University Medical Center Utrecht, Utrecht, The Netherlands

3Department of Equine Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands

4Gastroenterology & Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands

5Pathology, University Medical Center Utrecht, Utrecht, The Netherlands

6Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

*These authors have contributed equally to this work

Correspondence to:

Onno Kranenburg, email: [email protected]

Keywords: colorectal; budding; metastasis; consensus molecular subtypes; matrix metalloprotease

Received: July 15, 2017     Accepted: February 24, 2018     Published: April 13, 2018


Primary human colorectal tumors with a high stromal content have an increased capacity to metastasize. Cancer-associated fibroblasts (CAFs) promote metastasis, but the contribution of other stromal cell types is unclear. Here we searched for additional stromal cell types that contribute to aggressive tumor cell behavior. By making use of the ‘immunome compendium’—a collection of gene signatures reflecting the presence of specific immune cell-types—we show that macrophage signatures are most strongly associated with a high CAF content and with poor prognosis in multiple large cohorts of primary tumors and liver metastases. Co-culturing macrophages with patient-derived colonospheres promoted ‘budding’ of small clusters of tumor cells from the bulk. Immunohistochemistry showed that budding tumor clusters in stroma-rich areas of T1 colorectal carcinomas were surrounded by macrophages. In vitro budding was accompanied by reduced levels of the tight junction protein occludin, but OCLN mRNA levels did not change, nor did markers of epithelial mesenchymal transition. Budding was accompanied by nuclear accumulation of β-catenin, which was also observed in budding tumor cell clusters in situ. The NFκB inhibitor Sanguinarine resulted in a decrease in MMP7 protein expression and both NFκB inhibitor Sanguinarine and MMP inhibitor Batimastat prevented occludin degradation and budding.

We conclude that macrophages contribute to the aggressive nature of stroma-rich colon tumors by promoting an MMP-dependent pathway that operates in parallel to classical EMT and leads to tight junction disruption.

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