FUT9-Driven Programming of Colon Cancer Cells towards a Stem Cell-Like State

Athanasios Blanas,Maxime Kempers,Irene Van Der Haar Àvila,Sandra J Van Vliet,Laura Kruijssen,Anouk Zaal,Joost C Van Der Horst,Marko A Popovic,Mike De Kok

doi:10.3390/cancers12092580

Athanasios Blanas, Maxime Kempers + Show 7 more

Open Access

https://doi.org/10.3390/cancers12092580

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Abstract

Simple SummaryAberrant glycosylation, for instance heightened expression of fucosylated structures, is a frequent feature observed in tumor cells. Our paper outlines the role of aberrant fucosylation by the Fucosyltransferase 9 (FUT9) as a potent reprogramming factor marking the acquisition of a stem-like state both by murine and human colon cancer cells. Importantly, our study reinforces the implication of aberrant fucosylation in promoting tumor growth and resistance to chemotherapy in the context of colon cancer.Cancer stem cells (CSCs) are located in dedicated niches, where they remain inert to chemotherapeutic drugs and drive metastasis. Although plasticity in the CSC pool is well appreciated, the molecular mechanisms implicated in the regulation of cancer stemness are still elusive. Here, we define a fucosylation-dependent reprogramming of colon cancer cells towards a stem cell-like phenotype and function. De novo transcriptional activation of Fut9 in the murine colon adenocarcinoma cell line, MC38, followed by RNA seq-based regulon analysis, revealed major gene regulatory networks related to stemness. Lewisx, Sox2, ALDH and CD44 expression, tumorsphere formation, resistance to 5-FU treatment and in vivo tumor growth were increased in FUT9-expressing MC38 cells compared to the control cells. Likewise, human CRC cell lines highly expressing FUT9 displayed phenotypic features of CSCs, which were significantly impaired upon FUT9 knock-out. Finally, in primary CRC FUT9+ tumor cells pathways related to cancer stemness were enriched, providing a clinically meaningful annotation of the complicity of FUT9 in stemness regulation and may open new avenues for therapeutic intervention.

Highlights

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer type and the third cause of cancer-related deaths in both sexes worldwide [1]
Our results provide evidence that FUT9 dictates a stem cell-like fate in colon cancer cells both in mice and humans, suggesting a conserved role of this enzyme during malignant transformation and tumor fueling
Our results provide evidence that FUT9 is responsible for the hardwiring of both murine and human colon cancer cells towards a cancer stem cells (CSCs)-like transcriptional profile, phenotype and function, with major implications for tumor growth and resistance to chemotherapy

Summary

Introduction

Colorectal cancer (CRC) is the fourth most commonly diagnosed cancer type and the third cause of cancer-related deaths in both sexes worldwide [1]. Cancers 2020, 12, 2580 of cytotoxic chemotherapy for locally advanced and metastatic tumors [3]. The response to therapy remains largely heterogeneous [9] and therapy failure along with eventual relapse and metastatic disease has been attributed to a distinct subpopulation of tumor cells called cancer stem cells (CSCs) [10]. These cells exhibit unique properties, such as self-renewal, infinite division, pluripotency, reduced immunogenicity, resistance to conventional chemotherapy/radiotherapy and tumor-initiating capacity under adverse microenvironmental conditions. There is an immense need for the identification of novel molecular pathways defining CSC fate and hardwiring, which can in turn be harnessed for successful therapeutic targeting

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