TY - JOUR
T1 - The miR-371373 cluster represses colon cancer initiation and metastatic colonization by inhibiting the TGFBR2/ID1 signaling axis
AU - Ullmann, Pit
AU - Rodriguez, Fabien
AU - Schmitz, Martine
AU - Meurer, Steffen K.
AU - Qureshi-Baig, Komal
AU - Felten, Paul
AU - Ginolhac, Aurelien
AU - Antunes, Laurent
AU - Frasquilho, Sonia
AU - Zügel, Nikolaus
AU - Weiskirchen, Ralf
AU - Haan, Serge
AU - Letellier, Elisabeth
N1 - Funding Information:
We would like to thank all the contributing surgeons and nurses from the Centre Hospitalier du Luxembourg, the Centre Hospitalier Emile Mayrisch, and the Clinical and Epidemiological Investigation Centre of the Luxembourg Institute of Health (LIH) for their work with the patients. The authors would also like to thank their collaborators at the Integrated Biobank of Luxembourg (IBBL), particularly Fay Betsou and Nikolai Goncharenko for the overall set-up of the patient sample collection and RNA extraction as well as Yervan Kar-apetyan and Bénédicte Culot for their help with histopathology analysis. We are also grateful to Djalil Coowar and Marthe Schmit for managing the animal facility of the University of Luxembourg. We are grateful to all the members of the Genomics Research Unit of the LIH for performing the microarray experiments and for providing bioinformatics support. We would also like to thank Arnaud Muller from the LIH for his help with IPA and GSEA. Finally, we would like to thank Lasse Sinkkonen and Stephanie Kreis from the LSRU as well as Christelle Bahlawane from the LSRU/IBBL for additional help and critical discussions. This project was supported by the Fonds National de la Recherche (FNR) Luxembourg (E. Letellier received grant C16/BM/11282028; K. Qureshi-Baig received grant AFR/3093113; and P. Ullmann received grant AFR/
Funding Information:
We would like to thank all the contributing surgeons and nurses from the Centre Hospitalier du Luxembourg, the Centre Hospitalier Emile Mayrisch, and the Clinical and Epidemiological Investigation Centre of the Luxembourg Institute of Health (LIH) for their work with the patients. The authors would also like to thank their collaborators at the Integrated Biobank of Luxembourg (IBBL), particularly Fay Betsou and Nikolai Goncharenko for the overall set-up of the patient sample collection and RNA extraction as well as Yervan Kar-apetyan and Benedicte Culot for their help with histopathology analysis. We are also grateful to Djalil Coowar and Marthe Schmit for managing the animal facility of the University of Luxembourg. We are grateful to all the members of the Genomics Research Unit of the LIH for performing the microarray experiments and for providing bioinformatics support. We would also like to thank Arnaud Muller from the LIH for his help with IPA and GSEA. Finally, we would like to thank Lasse Sinkkonen and Stephanie Kreis from the LSRU as well as Christelle Bahlawane from the LSRU/IBBL for additional help and critical discussions. This project was supported by the Fonds National de la Recherche (FNR) Luxembourg (E. Letellier received grant C16/BM/11282028; K. Qureshi-Baig received grant AFR/3093113; and P. Ullmann received grant AFR/ 7855578) and by the Fondation Cancer (E. Letellier and S. Haan received grant F1R-LSC-PAU-13HY2C). K. Qureshi-Baig and P. Ullmann were also supported by the Fondation du Pelican de Mie and Pierre Hippert-Faber under the aegis of the Fondation de Luxembourg. R. Weiskirchen is supported by grants from the German Research Foundation (DFG, SFB/TRR 57, projects P13 and Q3) and received a grant from the Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at the RWTH Aachen University (IZKF Aachen, Project E03-1).
Funding Information:
7855578) and by the Fondation Cancer (E. Letellier and S. Haan received grant F1R-LSC-PAU-13HY2C). K. Qureshi-Baig and P. Ullmann were also supported by the Fondation du Pélican de Mie and Pierre Hippert-Faber under the aegis of the Fondation de Luxembourg. R. Weiskirchen is supported by grants from the German Research Foundation (DFG, SFB/TRR 57, projects P13 and Q3) and received a grant from the Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at the RWTH Aachen University (IZKF Aachen, Project E03-1).
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/7/15
Y1 - 2018/7/15
N2 - The vast majority of colorectal cancer–related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different colorectal cancer cell lines and recently established primary cultures enriched in colon cancer stem cells, also known as tumor-initiating cells (TIC), to identify genes and miRNAs with regulatory functions in colorectal cancer progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, TGFb signaling activity, and reduced expression of the miR-371373 cluster compared with nonmetastatic cultures. TGFb receptor 2 (TGFBR2) and aldehyde dehydrogenase A1 (ALDH1A1) were identified as important target genes of the miR-371373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced in vitro self-renewal activity as well as lowered tumor initiation and metastatic outgrowth capacity in vivo following stable overexpression of the miR-371373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371373 and ID1. Altogether, our results establish the miR-371373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization. Significance: These findings establish the miR-371~373/TGFBR2/ID1 signaling axis as a novel mechanismregulating self-renewal of tumor-initiating cell and metastatic colonization, potentially opening new concepts for therapeutic targeting of cancer metastasis. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3793/F1.large.jpg.
AB - The vast majority of colorectal cancer–related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different colorectal cancer cell lines and recently established primary cultures enriched in colon cancer stem cells, also known as tumor-initiating cells (TIC), to identify genes and miRNAs with regulatory functions in colorectal cancer progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, TGFb signaling activity, and reduced expression of the miR-371373 cluster compared with nonmetastatic cultures. TGFb receptor 2 (TGFBR2) and aldehyde dehydrogenase A1 (ALDH1A1) were identified as important target genes of the miR-371373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced in vitro self-renewal activity as well as lowered tumor initiation and metastatic outgrowth capacity in vivo following stable overexpression of the miR-371373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371373 and ID1. Altogether, our results establish the miR-371373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization. Significance: These findings establish the miR-371~373/TGFBR2/ID1 signaling axis as a novel mechanismregulating self-renewal of tumor-initiating cell and metastatic colonization, potentially opening new concepts for therapeutic targeting of cancer metastasis. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3793/F1.large.jpg.
UR - http://www.scopus.com/inward/record.url?scp=85050696715&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-3003
DO - 10.1158/0008-5472.CAN-17-3003
M3 - Article
C2 - 29748374
AN - SCOPUS:85050696715
SN - 0008-5472
VL - 78
SP - 3793
EP - 3808
JO - Cancer Research
JF - Cancer Research
IS - 14
ER -