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Abstract
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 BRAFV 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.
Highlights
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
The transforming growth factor beta (TGFb) pathway was not perturbed in the tubular adenomas (TAs) organoid cultures, as all five cultures used in this study showed SMAD4 expression and induction of phopho-SMAD2 upon TGFb stimulation (Appendix Fig S1B and C)
Despite the fact that the consensus molecular subtypes (CMSs) of CRC cannot be identified based on unifying molecular markers currently used in the clinic, they represent biologically homogeneous groups, allowing the speculation that common underlying drivers are responsible for installing specific biological programs
Summary
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, suggesting the existence of unifying developmental drivers for each CMS. We investigated the role of such developmental drivers at the premalignant stage of distinct CRC subtypes and found that TGFb 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 TGFb is death by apoptosis. Our data indicate that TGFb signaling is already active in SSA precursor lesions and that TGFb is a critical cue for directing SSAs to the mesenchymal, poor-prognosis CMS4 of CRC
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