Runt related transcription factor-1 plays a central role in vessel co-option of colorectal cancer liver metastases

Miran Rada,Peter Metrakos,Peter Siegel,Sébastien Tabariès,Andrew R Reynolds,Stephanie Petrillo,Audrey Kapelanski-Lamoureux,Anthoula Lazaris

doi:10.1038/s42003-021-02481-8

Miran Rada, Peter Metrakos + Show 6 more

Open Access

https://doi.org/10.1038/s42003-021-02481-8

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Abstract

Colorectal cancer liver metastasis (CRCLM) has two major histopathological growth patterns: angiogenic desmoplastic and non-angiogenic replacement. The replacement lesions obtain their blood supply through vessel co-option, wherein the cancer cells hijack pre-existing blood vessels of the surrounding liver tissue. Consequentially, anti-angiogenic therapies are less efficacious in CRCLM patients with replacement lesions. However, the mechanisms which drive vessel co-option in the replacement lesions are unknown. Here, we show that Runt Related Transcription Factor-1 (RUNX1) overexpression in the cancer cells of the replacement lesions drives cancer cell motility via ARP2/3 to achieve vessel co-option. Furthermore, overexpression of RUNX1 in the cancer cells is mediated by Transforming Growth Factor Beta-1 (TGFβ1) and thrombospondin 1 (TSP1). Importantly, RUNX1 knockdown impaired the metastatic capability of colorectal cancer cells in vivo and induced the development of angiogenic lesions in liver. Our results confirm that RUNX1 may be a potential target to overcome vessel co-option in CRCLM.

Highlights

Colorectal cancer liver metastasis (CRCLM) has two major histopathological growth patterns: angiogenic desmoplastic and non-angiogenic replacement
Angiogenesis has been reported as an essential step in the growth of metastatic tumors, which is driven by vascular endothelial growth factor-A (VEGF-A)[5,6]
RUNX1 is overexpressed in vessel co-opting CRCLM tumors

Summary

Introduction

Colorectal cancer liver metastasis (CRCLM) has two major histopathological growth patterns: angiogenic desmoplastic and non-angiogenic replacement. The replacement lesions obtain their blood supply through vessel co-option, wherein the cancer cells hijack preexisting blood vessels of the surrounding liver tissue. Anti-angiogenic therapies are less efficacious in CRCLM patients with replacement lesions. We show that Runt Related Transcription Factor-1 (RUNX1) overexpression in the cancer cells of the replacement lesions drives cancer cell motility via ARP2/3 to achieve vessel co-option. RUNX1 knockdown impaired the metastatic capability of colorectal cancer cells in vivo and induced the development of angiogenic lesions in liver. Surgical treatment is not possible in 80% of colorectal cancer liver metastasis (CRCLM) cases and the patients are left with palliative options, mainly consisting of systemic treatment with palliative intent[2,4]. The mechanisms that limit the therapeutic efficacy of anti-angiogenic therapy in patients are still unclear. Vessel co-option has been reported in different cancers, for instance, liver metastases[14], non–small cell lung cancer[15], lung metastases[16,17], lymph node metastasis[18,19] and hepatocellular carcinoma[20]

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