The notch target gene HEYL modulates metastasis forming capacity of colorectal cancer patient-derived spheroid cells in vivo | BMC Cancer | Full Text

The notch target gene HEYL modulates metastasis forming capacity of colorectal cancer patient-derived spheroid cells in vivo | BMC Cancer | Full Text

BMC Cancer

The notch target gene HEYL modulates metastasis forming capacity of colorectal cancer patient-derived spheroid cells in vivo

• Sarah Weber, 
• Sebastian E. Koschade, 
• Christopher M. Hoffmann, 
• Taronish D. Dubash, 
• Klara M. Giessler, 
• Sebastian M. Dieter, 
• Friederike Herbst, 
• Hanno Glimm & 
• Claudia R. Ball 

BMC Cancer volume 19, Article number: 1181 (2019) Cite this article

Abstract

Background

While colorectal cancer (CRC) patients with localized disease have a favorable prognosis, the five-year-survival rate in patients with distant spread is still below 15%. Hence, a detailed understanding of the mechanisms regulating metastasis formation is essential to develop therapeutic strategies targeting metastasized CRC. The notch pathway has been shown to be involved in the metastatic spread of various tumor entities; however, the impact of its target gene HEYL remains unclear so far.

Methods

In this study, we functionally assessed the association between high HEYL expression and metastasis formation in human CRC. Therefore, we lentivirally overexpressed HEYL in two human patient-derived CRC cultures differing in their spontaneous metastasizing capacity and analyzed metastasis formation as well as tumor cell dissemination into the bone marrow after xenotransplantation into NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice.

Results

HEYL overexpression decreased tumor cell dissemination and the absolute numbers of formed metastases in a sub-renal capsular spontaneous metastasis formation model, addressing all steps of the metastatic cascade. In contrast, metastatic capacity was not decreased following intrasplenic xenotransplantation where the cells are placed directly into the blood circulation.

Conclusion

These results suggest that HEYL negatively regulates metastasis formation in vivo presumably by inhibiting intravasation of metastasis-initiating cells.