University Medical Center Utrecht - Clevers Group - Hubrecht Institute

Hans Clevers is Head of pharma Research and Early Development (pRED) of Roche, Basel Switzerland, since March 2022. He was group leader at the Hubrecht Institute from 2002 until March 2022 and currently he is advisor/guest researcher at the Hubrecht Institute.

The Organoid group, previously Clevers group, studies the molecular mechanisms of tissue development and cancer of various organs using organoids made from adult Lgr5 stem cells.

Tcf as Wnt effector

In 1991, we reported the cloning of a T cell specific transcription factor that we termed TCF1 (1). Related genes exist in genomes throughout the animal kingdom. We have shown in frogs (4), flies (7) and worms (11) that the TCF proteins constitute the effectors of the canonical Wnt pathway. Upon Wnt signaling, ß-catenin binds and activates nuclear TCFs by providing a trans-activation domain. For these studies, we designed the widely used pTOPFLASH Wnt reporters. In the absence of Wnt signaling, we found that Tcf factors associate with proteins of the Groucho family of transcriptional repressors to repress target gene transcription (9).

Wnt signaling in cancer

The tumor suppressor protein APC forms the core of a cytoplasmic complex which binds ß-catenin and targets it for degradation in the proteasome. In APC-deficient colon carcinoma cells, we demonstrated that ß-catenin accumulates and is constitutively complexed with the TCF family member TCF4, providing a molecular explanation for the initiation of colon cancer (5).