Differential WNT activity in colorectal cancer confers limited tumorigenic potential and is regulated by MAPK signaling.
Colorectal cancers (CRC) express the WNT effector protein β-catenin in a heterogeneous subcellular pattern rather than uniformly in the nucleus. In this study, we investigated this important aspect of molecular heterogeneity in CRCs by analyzing its basis and relationship with tumor-initiating capability. CRC cells with the highest WNT levels showed only a marginal increase in tumor initiation capacity. Notably, high WNT activity correlated with a coincident activation of robust mitogen-activated protein kinase (MAPK) signaling, which when upregulated by KRAS expression or downregulated by epidermal growth factor receptor inhibition elicited parallel effects on WNT activity. These findings suggested that on its own high WNT activity may not be a reliable signifier of tumor-initiating potential or stem-like potential. Furthermore, they suggest that MAPK signaling is a critical modifier of intratumoral heterogeneity that contributes significantly to determining the impact of WNT activity on stemness phenotypes in colon cancer cells.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. david.horst@med.uni-muenchen.de
David
D
Horst
Justina
J
Chen
Teppei
T
Morikawa
Shuji
S
Ogino
Thomas
T
Kirchner
Ramesh A
RA
Shivdasani
D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
C495270:CTNNB1 protein, human; D051153:Wnt Proteins; D051176:beta Catenin