Bidirectional tumor/stroma crosstalk promotes metastasis in mesenchymal colorectal cancer

• Published in: Oncogene Vol. 39; no. 12; pp. 2453 - 2466
• Main Authors: Ouahoud, Sarah, Voorneveld, Philip W., van der Burg, Lennart R. A., de Jonge-Muller, Eveline S. M., Schoonderwoerd, Mark J. A., Paauwe, Madelon, de Vos, Thijs, de Wit, Sophie, van Pelt, Gabi W., Mesker, Wilma E., Hawinkels, Lukas J.A.C., Hardwick, James C. H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2020; Nature Publishing Group
• Subjects: 13/51; 14/34; 14/63; 38/61; 42/41; 59; 59/5; 631/67/1504/1885; 631/67/327; 631/67/70; 64/60; Animals; Apoptosis; Bone Morphogenetic Protein 2 - metabolism; Cancer; Cancer-Associated Fibroblasts - metabolism; Care and treatment; Cell Biology; Cell Line; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Complications and side effects; Culture Media, Conditioned; Fibroblasts; Gene expression; Genetic aspects; Health aspects; HT29 Cells; Human Genetics; Humans; Internal Medicine; Invasiveness; Liver Neoplasms - secondary; Male; Medical prognosis; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Metastasis; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Oncology; Risk factors; Smad4 protein; Smad4 Protein - metabolism; Stroma; Stromal Cells - metabolism; Survival Rate; TNF-Related Apoptosis-Inducing Ligand - metabolism; Tumor suppressor genes; Tumors; Netherlands
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-1157-z

Patients with the mesenchymal subtype colorectal cancer (CRC) have a poor prognosis, in particular patients with stroma-rich tumors and aberrant SMAD4 expression. We hypothesized that interactions between SMAD4-deficient CRC cells and cancer-associated fibroblasts provide a biological explanation. In transwell invasion assays, fibroblasts increased the invasive capacity of SMAD4-deficient HT29 CRC cells, but not isogenic SMAD4-proficient HT29 cells. A TGF-β/BMP-specific array showed BMP2 upregulation by fibroblasts upon stimulation with conditioned medium from SMAD4-deficient CRC cells, while also stimulating their invasion. In a mouse model for experimental liver metastasis, the co-injection of fibroblasts increased metastasis formation of SMAD4-deficient CRC cells ( p  = 0.02) but not that of SMAD4-proficient CRC cells. Significantly less metastases were seen in mice co-injected with BMP2 knocked-down fibroblasts. Fibroblast BMP2 expression seemed to be regulated by TRAIL, a factor overexpressed in SMAD4-deficient CRC cells. In a cohort of 146 stage III CRC patients, we showed that patients with a combination of high stromal BMP2 expression and the loss of tumor SMAD4 expression had a significantly poorer overall survival (HR 2.88, p  = 0.04). Our results suggest the existence of a reciprocal loop in which TRAIL from SMAD4-deficient CRC cells induces BMP2 in fibroblasts, which enhances CRC invasiveness and metastasis.