TY - JOUR
T1 - FUT9-Driven Programming of Colon Cancer Cells towards a Stem Cell-Like State
AU - Blanas, Athanasios
AU - Zaal, Anouk
AU - van der Haar Àvila, Irene
AU - Kempers, Maxime
AU - Kruijssen, Laura
AU - de Kok, Mike
AU - Popovic, Marko A
AU - van der Horst, Joost C
AU - J van Vliet, Sandra
N1 - Funding Information: Funding: This work was supported by the European Union (Marie-Curie European Training Network), GlyCoCan project, Grant number 676,421 to A.B., the Cancer Center Amsterdam (CCA), Grant number CCA2016-5-29 to A.Z., the European Research Council, Glycotreat, Grant number 339977 to L.K. and the Dutch Cancer Society (KWF), Grant numbers 2014-6779 and 12,420 to J.C.v.d.H., I.v.d.H.A. and S.J.v.V. Publisher Copyright: © 2020 by the authors. Licensee MDPI, Basel, Switzerland. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/9/10
Y1 - 2020/9/10
N2 - 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.
AB - 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.
KW - Colon cancer
KW - Drug resistance
KW - Fucosylation
KW - Glycosylation
KW - Pluripotency
KW - Stem cells
UR - http://www.scopus.com/inward/record.url?scp=85091347856&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/cancers12092580
DO - https://doi.org/10.3390/cancers12092580
M3 - Article
C2 - 32927726
SN - 2072-6694
VL - 12
SP - 1
EP - 26
JO - Cancers
JF - Cancers
IS - 9
M1 - 2580
ER -