The role of TCF7L2 in colorectal tumorigenesis - oncogene or tumor suppressor?

• Applicant: Professor Dr. Andreas Hecht
• Subject Area: Cell Biology ; Evolutionary Cell and Developmental Biology (Zoology) ; Hematology, Oncology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 315268620

The transcription factor TCF7L2 (alias: TCF4) is a binding partner of beta-catenin and key nuclear effector of Wnt/beta-catenin signaling. TCF7L2 is essential for intestinal development and in adult tissue homeostasis. Paradoxically, up to 30% of human colorectal tumors carry mutations in the TCF7L2 gene. This makes TCF7L2 one of the most frequently mutated genes in colorectal cancer. Three different TCF7L2 mutational patterns are apparent: selective inactivation of a subset of TCF7L2 splice variants, 50% reduction of TCF7L2 expression by inactivation of one gene copy, and biallelic deletion. All three patterns lead to partial or complete loss of TCF7L2 function which is at odds with the absolute requirements for TCF7L2 in the healthy intestine and its role as driver of oncogene expression. Hence, the overall goal of the proposed studies is to clarify this apparent contradiction and to shed light on the pro- and anti-tumorigenic functions of TCF7L2 in colorectal cancer. Specifically we will test three hypotheses that could explain the occurrence of TCF7L2 mutational patterns and their impact on colorectal carcinogenesis. First, mutations that reduce the overall expression of TCF7L2 and particular TCF7L2 isoforms could provide a growth advantage to tumor cells by blocking the pro-differentiation function of Wnt/beta-catenin signaling while retaining its mitogenic activity. Second, the functional substitution of TCF7L2 by other TCF/LEF proteins which are pathologically upregulated in colorectal cancer cells, could allow the partial or complete inactivation of TCF7L2. Third, metastatic colorectal tumors might be able to tolerate complete TCF7L2 deletion because they might have acquired independence of beta-catenin/TCF7L2 driven transcription due to activation of Hedgehog/GLI signaling or overexpression of the intestinal stem cell transcription factor ASCL2. To test our hypotheses, we will use CRISPR/Cas9-mediated genome editing of colorectal cancer cells and intestinal organoid cultures from genetically modified mouse models to reconstruct the mutational patterns of TCF7L2 observed in human tumors. We will investigate how alterations of the TCF7L2 genotype affect tumor-relevant phenotypic traits, whether the TCF7L2 gene is essential in colorectal cancer cells, and whether upregulation of TCF/LEF family members, ASCL2 or Hedgehog/GLI activity can compensate for loss of TCF7L2. Bioinformatic analyses of publicly available transcriptome and genome data sets will be used as an independent strategy to interrogate relationships between TCF7L2 mutations, the expression of TCF/LEF family members, ASCL2, signature genes specifying Hedgehog/GLI activity, and as yet unknown features. Overall, the proposed studies will lead to novel insights into the biology of TCF7L2 and the molecular pathology of colorectal cancer. Thereby, they will provide the necessary basis for a rational evaluation of the beta-catenin::TCF7L2 complex as a suitable therapeutic target.

• DFG Programme: Research Grants