The tumor suppressor CDX2 opposes pro-metastatic biomechanical modifications of colon cancer cells through organization of the actin cytoskeleton.
The vast majority of cancer deaths are caused by the formation of metastases rather than the primary tumor itself. Despite this clinical importance, the molecular and cellular events that support the dissemination of cancer cells are not yet fully unraveled. We have previously shown that CDX2, a homeotic transcription factor essential for gut development, acts as a colon-specific tumor suppressor and opposes metastasis. Here, using a combination of biochemical, biophysical, and immunofluorescence techniques, we further investigated the mechanisms promoted by CDX2 that might antagonize tumor cell dissemination. We found that CDX2 expression regulates the transcription of RHO GEFs, thereby activating RHO signaling cascades that lead to reorganization of the actin cytoskeleton and enhanced adherent junctions. Accordingly, we observed by atomic force microscopy (AFM) that colon cancer cells expressing CDX2 are less deformable, a feature that has been shown to correlate with poor metastatic potential. Thus, this study illustrates how the loss of expression of a transcription factor during colon cancer progression modifies the biomechanical characteristics of tumor cells and hence facilitates invasion and metastasis.
INSERM UMR_S1113, Strasbourg, F-67200, France; FMTS, Université de Strasbourg, Strasbourg, F-67000, France.
Nadine
N
Platet
INSERM UMR_S1113, Strasbourg, F-67200, France; FMTS, Université de Strasbourg, Strasbourg, F-67000, France.
Isabelle
I
Hinkel
INSERM UMR_S1121, Strasbourg, F-67085, France; FMTS, Université de Strasbourg, Strasbourg, F-67000, France; Faculté de Chirurgie Dentaire, Université de Strasbourg, Strasbourg, F-67000, France.
Ludovic
L
Richert
INSERM UMR_S1109, Strasbourg, F-67200, France; FMTS, Université de Strasbourg, Strasbourg, F-67000, France.
Devadarssen
D
Murdamoothoo
INSERM UMR_S1113, Strasbourg, F-67200, France; FMTS, Université de Strasbourg, Strasbourg, F-67000, France.
Ahlam
A
Moufok-Sadoun
INSERM UMR_S1113, Strasbourg, F-67200, France; FMTS, Université de Strasbourg, Strasbourg, F-67000, France.
Marie
M
Vanier
INSERM UMR_S1121, Strasbourg, F-67085, France; FMTS, Université de Strasbourg, Strasbourg, F-67000, France; Faculté de Chirurgie Dentaire, Université de Strasbourg, Strasbourg, F-67000, France.
Philippe
P
Lavalle
INSERM UMR_S1113, Strasbourg, F-67200, France; FMTS, Université de Strasbourg, Strasbourg, F-67000, France.
Christian
C
Gaiddon
INSERM UMR_S1121, Strasbourg, F-67085, France; FMTS, Université de Strasbourg, Strasbourg, F-67000, France; Faculté de Chirurgie Dentaire, Université de Strasbourg, Strasbourg, F-67000, France.
Dominique
D
Vautier
INSERM UMR_S1113, Strasbourg, F-67200, France; FMTS, Université de Strasbourg, Strasbourg, F-67000, France.
Jean-Noel
JN
Freund
INSERM UMR_S1113, Strasbourg, F-67200, France; FMTS, Université de Strasbourg, Strasbourg, F-67000, France. Electronic address: isabelle.gross@inserm.fr.
Isabelle
I
Gross
D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000473:pathology; D022005:Adherens Junctions / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001696:Biomechanical Phenomena; D000071616:CDX2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D019073:HT29 Cells; D006801:Humans; D008822:Mice, Transgenic; D018625:Microscopy, Atomic Force; D009362:Neoplasm Metastasis; D010641:Phenotype; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C487514:Cdx2 protein, mouse; D051567:Proto-Oncogene Proteins c-vav; D025521:Tumor Suppressor Proteins; C496621:VAV3 protein, human; D020741:rho GTP-Binding Proteins
Cellular stiffness; Colorectal cancer; Homeobox gene; Metastasis; Stress fibers