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Background Epithelial-mesenchymal transition (EMT) is an embryonic programme implicated in cancer stem cells, metastasis and therapeutic resistance. Its role in cancer progression remains controversial because the transition can be partial or complete in different models and contexts. Methods Using human colon cancer DLD-1 cells, we engineered a cell line with a single-copy of Snail that was doxycycline-inducible and compared it to existing EMT models in DLD-1. The effect of Snail upregulation was characterised functionally, morphologically, and by transcriptional profiling and protein expression. Results Induction with doxycycline increased Snail expression to a level similar to that observed in cancer cell lines spontaneously expressing Snail and results in partial EMT. In comparison, higher levels of overexpression arising from introduction of episomal-Snail, results in complete EMT. DLD-1 cells with partial EMT show chemoresistance in vitro, increased tumour growth in vivo and decreased apoptosis. Conclusions These findings highlight that the amount of bioavailable Snail can dictate phenotypic outcome and that partial EMT may be a preferred outcome of models operating within a natural range of Snail overexpression.

Lrig1, a transmembrane glycoprotein, has previously been shown to inhibit ErbB signalling. Jensen and colleagues show that Lrig1 controls the size of the intestinal stem-cell niche by modulating the amplitude of ErbB signalling. Thus, ErbB activation acts in concert with Wnt, Notch and Bmpr inhibition, to modulate stem-cell proliferation in the crypt. Maintenance of adult tissues is carried out by stem cells and is sustained throughout life in a highly ordered manner 1 , 2 . Homeostasis within the stem-cell compartment is governed by positive- and negative-feedback regulation of instructive extrinsic and intrinsic signals 3 , 4 . ErbB signalling is a prerequisite for maintenance of the intestinal epithelium following injury and tumour formation 5 , 6 . As ErbB-family ligands and receptors are highly expressed within the stem-cell niche 7 , we hypothesize that strong endogenous regulators must control the pathway in the stem-cell compartment. Here we show that Lrig1, a negative-feedback regulator of the ErbB receptor family 8 , 9 , 10 , is highly expressed by intestinal stem cells and controls the size of the intestinal stem-cell niche by regulating the amplitude of growth-factor signalling. Intestinal stem-cell maintenance has so far been attributed to a combination of Wnt and Notch activation and Bmpr inhibition 11 , 12 , 13 . Our findings reveal ErbB activation as a strong inductive signal for stem-cell proliferation. This has implications for our understanding of ErbB signalling in tissue development and maintenance and the progression of malignant disease.

Alzheimer's drugs for cancer? Notch genes encode a range of membrane receptors that regulate cell-fate decisions by influencing communication between adjacent cells. Two groups now report the involvement of Notch signals in controlling the fate of intestinal epithelial tissue. In addition, blockade of the Notch pathway with the γ-secretase inhibitor DBZ halted growth of adenomas (polyps) in the small intestine and colon. Various γ-secretase inhibitors are being developed for the treatment of Alzheimer's disease; this new work suggests that they might also be used to treat colorectal cancers. The self-renewing epithelium of the small intestine is ordered into stem/progenitor crypt compartments and differentiated villus compartments. Recent evidence indicates that the Wnt cascade is the dominant force in controlling cell fate along the crypt–villus axis 1 . Here we show a rapid, massive conversion of proliferative crypt cells into post-mitotic goblet cells after conditional removal of the common Notch pathway transcription factor CSL/RBP-J (ref. 2 ). We obtained a similar phenotype by blocking the Notch cascade with a γ-secretase inhibitor. The inhibitor also induced goblet cell differentiation in adenomas in mice carrying a mutation of the Apc tumour suppressor gene. Thus, maintenance of undifferentiated, proliferative cells in crypts and adenomas requires the concerted activation of the Notch and Wnt cascades. Our data indicate that γ-secretase inhibitors, developed for Alzheimer's disease, might be of therapeutic benefit in colorectal neoplastic disease.

Maintenance of adult tissues is carried out by stem cells and is sustained throughout life in a highly ordered manner (1,2). Homeostasis within the stem-cell compartment is governed by positive- and negative-feedback regulation of instructive extrinsic and intrinsic signals (3,4). ErbB signalling is a prerequisite for maintenance of the intestinal epithelium following injury and tumour formation (5,6). As ErbB-family ligands and receptors are highly expressed within the stem-cell niche (7), we hypothesize that strong endogenous regulators must control the pathway in the stem-cell compartment. Here we show that Lrig1, a negative-feedback regulator of the ErbB receptor family (8-10), is highly expressed by intestinal stem cells and controls the size of the intestinal stem-cell niche by regulating the amplitude of growth-factor signalling. Intestinal stem-cell maintenance has so far been attributed to a combination of Wnt and Notch activation and Bmpr inhibition (11-13). Our findings reveal ErbB activation as a strong inductive signal for stem-cell proliferation. This has implications for our understanding of ErbB signalling in tissue development and maintenance and the progression of malignant disease.

The majority of human colorectal cancers (CRCs) are initiated by mutations arising in the adenomatous polyposis coli (APC) tumour suppressor gene. However, a new class of non‐ APC mutated CRCs has been defined that have a serrated histopathology and carry the V600E BRAF oncogene. Here we have investigated the pathogenesis of serrated CRCs by expressing V600E Braf in the proliferative cells of the mouse gastrointestinal tract. We show that the oncogene drives an initial burst of Mek‐dependent proliferation, leading to the formation of hyperplastic crypts. This is associated with β‐catenin nuclear localization by a mechanism involving Mapk/Erk kinase (Mek)‐dependent, Akt‐independent phosphorylation of Gsk3β. However, hyperplastic crypts remain dormant for prolonged periods due to the induction of crypt senescence accompanied by upregulation of senescence‐associated β‐galactosidase and p16 Ink4a . We show that tumour progression is associated with down‐regulation of p16 Ink4a through enhanced CpG methylation of exon 1 and knockout of Cdkn2a confirms this gene is a barrier to tumour progression. Our studies identify V600E BRAF as an early genetic driver mutation in serrated CRCs and indicate that, unlike APC ‐mutated cancers, this subtype arises by the bypassing of a V600E Braf driven oncogene‐induced senescence programme.

The majority of human colorectal cancers (CRCs) are initiated by mutations arising in the adenomatous polyposis coli (APC) tumour suppressor gene. However, a new class of non‐APC mutated CRCs has been defined that have a serrated histopathology and carry the V600EBRAF oncogene. Here we have investigated the pathogenesis of serrated CRCs by expressing V600EBraf in the proliferative cells of the mouse gastrointestinal tract. We show that the oncogene drives an initial burst of Mek‐dependent proliferation, leading to the formation of hyperplastic crypts. This is associated with β‐catenin nuclear localization by a mechanism involving Mapk/Erk kinase (Mek)‐dependent, Akt‐independent phosphorylation of Gsk3β. However, hyperplastic crypts remain dormant for prolonged periods due to the induction of crypt senescence accompanied by upregulation of senescence‐associated β‐galactosidase and p16Ink4a. We show that tumour progression is associated with down‐regulation of p16Ink4a through enhanced CpG methylation of exon 1 and knockout of Cdkn2a confirms this gene is a barrier to tumour progression. Our studies identify V600EBRAF as an early genetic driver mutation in serrated CRCs and indicate that, unlike APC‐mutated cancers, this subtype arises by the bypassing of a V600EBraf driven oncogene‐induced senescence programme.

Colorectal cancer is thought to arise when the mutational burden of the clonal population of stem cells within a colonic crypt exceeds a certain threshold. Therefore, quantification of the fixation and subsequent expansion of somatic mutations in histologically normal epithelium is key to understanding colorectal cancer initiation. Here, using immunohistochemistry, loss of the histone demethylase KDM6A in normal human colonic epithelium is visualised. Interpretation of the age-related behaviour of KDM6A-negative clones revealed significant competitive advantage in intra-crypt dynamics. Further, subsequent clonal expansion into multi-crypt patches was quantified to reveal a significant 5-fold increase in crypt fission rate. To accomodate the local accumulation of new crypts, the role of crypt fusion was considered. However, no compensatory increase in fusion rate was found. Instead, evidence for crypt diffusion is presented and proposed as a means of accommodating clonal expansions. The threshold fission rate at which diffusion fails to accommodate new crypts, and which may promote polyp growth, is defined. Competing Interest Statement The authors have declared no competing interest.