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Biofabricated patient-derived mini-colons as next-generation colorectal cancer organoids

ABSTRACT: The compromise to reduce, replace, and refine (3Rs) animal usage in cancer research demands the development of biologically capable ex vivo cancer models. The establishment of three-dimensional organoid-based systems has paved the way in this direction by bringing some realistic in vivo features to the in vitro context. However, faithful modeling of cancer requires a degree of tissue-level organization, multi-cellular diversity, biological durability, and experimental flexibility that far exceeds the capabilities of any existing in vitro systems. Here we implemented tissue engineering and microfabrication technologies to develop topobiologically complex patient-specific avatars of colorectal cancer able to overcome those limitations. These miniature tissues consist of long-lived gut-like-shaped healthy colon epithelia (“mini-colons”) that allow the stable integration of cancer cells and their native tumor microenvironment on a platform designed for the real-time high-resolution evaluation of cellular dynamics. This provides an unprecedented repertoire of ex vivo experimental possibilities, which we illustrate through different applications, including the discovery of a cancer associated fibroblast-triggered mechanism driving colorectal cancer invasion. As a whole, our mini-colon system pushes the boundaries of ex vivo cancer research in both basic and pre-clinical settings.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226723 | GEO | 2024/05/01

REPOSITORIES: GEO

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Spatiotemporally resolved ex vivo colorectal cancer development in engineered mini-colons (scRNA-Seq)

Project description:Here we developed topobiologically complex mini-colons able to undergo tumorigenesis ex vivo by integrating microfabrication, optogenetic, and tissue engineering approaches. With this system, tumorigenic transformation can be spatiotemporally controlled by directing oncogenic activation through blue-light exposure, and emerging colon tumors can be tracked in real-time with single-cell resolution for several weeks without breaking the culture. These induced mini-colons display rich intra- and inter-tumoral diversity and recapitulate key pathophysiological hallmarks displayed by colorectal tumors in vivo. By fine-tuning cell-intrinsic and extrinsic parameters, mini-colons can be leveraged to unveil tumorigenic determinants, including dietary patterns, microbiota-derived metabolites, and pharmacological therapies.

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Spatiotemporally resolved ex vivo colorectal cancer development in engineered mini-colons (RNA-Seq Gpx2 KD)

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Spatiotemporally resolved ex vivo colorectal cancer development in engineered mini-colons (RNA-Seq AKP lines)

2024-02-24 | GSE221159 | GEO

Mouse slurry colons 2 weeks

Project description:Defining the complex role of the microbiome in colorectal cancer (CRC) and the discovery of novel, pro-tumorigenic microbes are areas of active investigation. In the present study, culturing and reassociation experiments revealed that toxigenic strains of Clostridioides difficile drove the tumorigenic phenotype of a subset of CRC patient-derived mucosal slurries in germ-free ApcMin/+ mice. Tumorigenesis was dependent on the C. difficile toxin TcdB and was associated with induction of Wnt signaling, reactive oxygen species, and pro-tumorigenic mucosal immune responses marked by infiltration of activated myeloid cells and interleukin-17 (IL-17)-producing lymphoid and innate lymphoid cell subsets. In vitro, purified TcdB directly induced DNA strand breaks at low picomolar concentrations. These findings suggest that chronic colonization with toxigenic C. difficile is a potential driver of CRC in patients. Comparing scRNA-seq from mouse colon tissue 2 weeks after inoculation with different bacterial slurries

2022-05-27 | GSE200969 | GEO

Comparison of HNF4 null to control colons

Project description:Background and Aims: HNF4a is a nuclear hormone receptor transcription factor that has been shown to be required for hepatocyte differentiation and development of the liver. It has also been implicated in regulating expression of genes that act in the epithelium of the lower gastrointestinal tract. This implied that HNF4a might be required for development of the gut. Methods: We generated mouse embryos in which HNF4a was ablated in the epithelial cells of the fetal colon using Cre-loxP technology. Embryos were examined using a combination of histology, immunohistochemistry, gene array and RT-PCR, and chromatin immunoprecipitation analyses to define the consequence of loss of HNF4a on colon development. Results: Embryos could be generated until E18.5 that lacked HNF4a in their colon. Although, early stages of colonic development occurred, HNF4a null colons failed to form normal crypts. In addition, goblet cell maturation was perturbed and expression of an array of genes that encode proteins with diverse roles in colon function was disrupted. Several genes whose expression in the colon was dependent on HNF4a contained HNF4a–binding sites sequences within putative transcriptional regulatory regions and a subset of these sites were occupied by HNF4a in vivo. Conclusion: HNF4a is a transcription factor that is essential for development of the mammalian colon, regulates goblet cell maturation and is required for expression of genes that control normal colon function and epithelial cell differentiation. Keywords: E18.5 FETAL HNF4 NULL COLONS

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Differential gene expression in the colons of mice lacking neuregulin-4

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2022-12-22 | GSE221575 | GEO

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2014-05-27 | GSE57969 | GEO

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Galectin-9 suppresses tumor growth of colon cancer in vitro and in vivo [in vivo CW 30]

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