TY - JOUR
T1 - SMAD4 suppresses WNt-driven dedifferentiation and oncogenesis in the differentiated gut epithelium
AU - Perekatt, Ansu O.
AU - Shah, Pooja P.
AU - Cheung, Shannon
AU - Jariwala, Nidhi
AU - Wu, Alex
AU - Gandhi, Vishal
AU - Kumar, Namit
AU - Feng, Qiang
AU - Patel, Neeket
AU - Chen, Lei
AU - Joshi, Shilpy
AU - Zhou, Anbo
AU - Taketo, M. Mark
AU - Xing, Jinchuan
AU - White, Eileen
AU - Gao, Nan
AU - Gatza, Michael L.
AU - Verzi, Michael P.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/9/1
Y1 - 2018/9/1
N2 - The cell of origin of colon cancer is typically thought to be the resident somatic stem cells, which are immortal and escape the continual cellular turnover characteristic of the intestinal epithelium. However, recent studies have identified certain conditions in which differentiated cells can acquire stem-like properties and give rise to tumors. Defining the origins of tumors will inform cancer prevention efforts as well as cancer therapies, as cancers with distinct origins often respond differently to treatments. We report here a new condition in which tumors arise from the differentiated intestinal epithelium. Inactivation of the differentiation-promoting transcription factor SMAD4 in the intestinal epithelium was surprisingly well tolerated in the short term. However, after several months, adenomas developed with characteristics of activated WNT signaling. Simultaneous loss of SMAD4 and activation of the WNT pathway led to dedifferentiation and rapid adenoma formation in differentiated tissue. Transcriptional profiling revealed acquisition of stem cell characteristics, and colabeling indicated that cells expressing differentiated enterocyte markers entered the cell cycle and reexpressed stem cell genes upon simultaneous loss of SMAD4 and activation of the WNT pathway. These results indicate that SMAD4 functions to maintain differentiated enterocytes in the presence of oncogenic WNT signaling, thus preventing dedifferentiation and tumor formation in the differentiated intestinal epithelium.
AB - The cell of origin of colon cancer is typically thought to be the resident somatic stem cells, which are immortal and escape the continual cellular turnover characteristic of the intestinal epithelium. However, recent studies have identified certain conditions in which differentiated cells can acquire stem-like properties and give rise to tumors. Defining the origins of tumors will inform cancer prevention efforts as well as cancer therapies, as cancers with distinct origins often respond differently to treatments. We report here a new condition in which tumors arise from the differentiated intestinal epithelium. Inactivation of the differentiation-promoting transcription factor SMAD4 in the intestinal epithelium was surprisingly well tolerated in the short term. However, after several months, adenomas developed with characteristics of activated WNT signaling. Simultaneous loss of SMAD4 and activation of the WNT pathway led to dedifferentiation and rapid adenoma formation in differentiated tissue. Transcriptional profiling revealed acquisition of stem cell characteristics, and colabeling indicated that cells expressing differentiated enterocyte markers entered the cell cycle and reexpressed stem cell genes upon simultaneous loss of SMAD4 and activation of the WNT pathway. These results indicate that SMAD4 functions to maintain differentiated enterocytes in the presence of oncogenic WNT signaling, thus preventing dedifferentiation and tumor formation in the differentiated intestinal epithelium.
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U2 - 10.1158/0008-5472.CAN-18-0043
DO - 10.1158/0008-5472.CAN-18-0043
M3 - Article
C2 - 29986996
AN - SCOPUS:85052702001
SN - 0008-5472
VL - 78
SP - 4878
EP - 4890
JO - Cancer Research
JF - Cancer Research
IS - 17
ER -