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Human cancers modeled in Genetically Engineered Mouse Models (GEMMs) can provide important mechanistic insights into the molecular basis of tumor development and enable testing of new intervention strategies. The inherent complexity of these models, with often multiple modified tumor suppressor genes and oncogenes, has hampered their use as preclinical models for validating cancer genes and drug targets. In our newly developed approach for the fast generation of tumor cohorts we have overcome this obstacle, as exemplified for three GEMMs; two lung cancer models and one mesothelioma model. Three elements are central for this system; (i) The efficient derivation of authentic Embryonic Stem Cells (ESCs) from established GEMMs, (ii) the routine introduction of transgenes of choice in these GEMM‐ESCs by Flp recombinase‐mediated integration and (iii) the direct use of the chimeric animals in tumor cohorts. By applying stringent quality controls, the GEMM‐ESC approach proofs to be a reliable and effective method to speed up cancer gene assessment and target validation. As proof‐of‐principle, we demonstrate that MycL1 is a key driver gene in Small Cell Lung Cancer. Synopsis The GEMM‐ESC approach describes and validates an improved method for generating mouse cancer models directly from embryonic stem cells. This technology speeds up the generation/modification of mouse models, while minimizing cost and breeding efforts. ESCs cultured in 2i medium show improved pluripotency and display equal genomic stability as ESCs cultured under classic conditions. Chimeric mice generated from GEMM‐ESCs are equally susceptible to tumors as compared to the parental strain, provided the chimeras display coat color contribution upwards of 70%. Experimental cohorts are generated on‐demand in less than 4 months without the need for any breeding. Controlled single copy integration of a transgene in the Col1a1 locus allows for robust reporter and oncogene expression in a mouse model for small cell lung cancer. Archived ESCs with complex genetic traits can serve as an important resource for the generation of new mouse models of cancer or for the validation of candidate cancer genes. Graphical Abstract The GEMM‐ESC approach describes and validates an improved method for generating mouse cancer models directly from embryonic stem cells. This technology speeds up the generation/modification of mouse models, while minimizing cost and breeding efforts.

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. It is currently believed that four to six crypt stem cells reside at the +4 position immediately above the Paneth cells in the small intestine; colon stem cells remain undefined. Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5, also known as Gpr49 ) was selected from a panel of intestinal Wnt target genes for its restricted crypt expression. Here, using two knock-in alleles, we reveal exclusive expression of Lgr5 in cycling columnar cells at the crypt base. In addition, Lgr5 was expressed in rare cells in several other tissues. Using an inducible Cre knock-in allele and the Rosa26-lacZ reporter strain, lineage-tracing experiments were performed in adult mice. The Lgr5-positive crypt base columnar cell generated all epithelial lineages over a 60-day period, suggesting that it represents the stem cell of the small intestine and colon. The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers. The mark of a stem cell The cells lining the small intestine and colon regenerate rapidly throughout life. Although they are among the best characterized of any stem cells for their functions, the isolation of pure or highly enriched intestinal epithelial stem cell populations has proved an elusive goal. Now it has been achieved. The Lgr5 gene, a target for the Wnt cell signalling system, has been identified as a unique single marker for stem cells in several adult tissues and in cancers. Lgr5 was first identified in colon cancer cells and is also found in pre-malignant mouse adenomas, raising the possibility that it might be a marker for cancer stem cells. The Lgr5 (also known as Gpr49 ) gene is identified as a unique, single marker gene for adult stem cells and provides the first lineage tracing data for long-lived pluripotent stem cells in the small intestine and colon. These findings will have great impact on stem cell and cancer research.

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.