TGFβ signaling directs serrated adenomas to the mesenchymal colorectal cancer subtype

The heterogeneous nature of colorectal cancer (CRC) complicates prognosis and is suggested to be a determining factor in the efficacy of adjuvant therapy for individual patients. Based on gene expression profiling, CRC is currently classified into four consensus molecular subtypes (CMSs), characterized by specific biological programs, thus suggesting the existence of unifying developmental drivers for each CMS. Using human organoid cultures, we investigated the role of such developmental drivers at the premalignant stage of distinct CRC subtypes and found that TGFβ plays an important role in the development of the mesenchymal CMS4, which is of special interest due to its association with dismal prognosis. We show that in tubular adenomas (TAs), which progress to classical CRCs, the dominating response to TGFβ is death by apoptosis. By contrast, induction of a mesenchymal phenotype upon TGFβ treatment prevails in a genetically engineered organoid culture carrying a BRAF V 600E mutation, constituting a model system for sessile serrated adenomas (SSAs). Our data indicate that TGFβ signaling is already active in SSA precursor lesions and that TGFβ is a critical cue for directing SSAs to the mesenchymal, poor‐prognosis CMS4 of CRC. Synopsis Sessile serrated adenomas (SSAs)—precursor lesions of the serrated neoplasia pathway to colorectal cancer (CRC)—are predicted to give rise to either the good‐ or the poor‐prognosis CRC consensus molecular subtype (CMS1 and CMS4, respectively). Organoid cultures from patient‐derived pre‐neoplastic lesions and genetically engineered organoid cultures present valuable model systems for early stage disease. An organoid culture genetically engineered to carry the BRAFV600E mutation served as a model system for the earliest stage of the serrated neoplasia pathway. A TGFβ signature separated patient‐derived tubular adenomas—precursor lesions of the classical path to CRC—from SSAs. High activity of the TGFβ signaling pathway was detected in SSAs that would likely have—judged by gene expression‐based prediction—developed to CMS4‐like CRCs. Graphical Abstract Sessile serrated adenomas (SSAs)—precursor lesions of the serrated neoplasia pathway to colorectal cancer (CRC)—are predicted to give rise to either the good‐ or the poor‐prognosis CRC consensus molecular subtype (CMS1 and CMS4, respectively).