Lineage reversion drives WNT independence in intestinal cancer

Han, Teng; Goswami, Sukanya; Hu, Yang; Tang, Fanying; Zafra, María Paz; Murphy, Charles J.; Cao, Zhen; Poirier, John T.; Khurana, Ekta; Elemento, Olivier; Hechtman, Jaclyn F.; Yaeger, Rona; Dow, Lukas E.

doi:10.1101/2020.01.22.914689

Cited by 3 publications

(2 citation statements)

References 65 publications

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“…This heterogeneity is readily visible in organoid morphology, and in this study we successfully utilize a neural network to characterize these morphological differences by automatically classifying organoids as “spheroid” or “budding” structures. Despite the biological processes underlying the formation of spheroid and budding organoids not being fully understood (Merenda, Fenderico, and Maurice 2019), these classifications can be used to determine differences between different conditions (Han et al 2020; Schwank et al 2013). Furthermore, our quantification of confocal images reveals that the spheroid and budding organoids have different tuft cell numbers, showing that classification is linked to biological implications.…”

Section: Discussionmentioning

confidence: 99%

Developmental pathways regulate cytokine-driven effector and feedback responses in the intestinal epithelium

Lindholm

Parmar

Drurey

et al. 2020

Preprint

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12The intestinal tract is a common site for infection, and it relies on an appropriate immune response to 13 defend against pathogens. The intestinal epithelium has an important role in effector responses, which 14 is coordinated by immune-type specific cytokines. It is incompletely understood how cytokines drive 15 epithelial responses. Here, using organoid-cytokine co-cultures, we provide a comprehensive analysis 16 of how key cytokines affect the intestinal epithelium, and relate this to in vivo infection models. We 17 use imaging, based on a convolutional neural network, and transcriptomic analysis to reveal that 18 cytokines use developmental pathways to define intestinal epithelial effector responses. For example, 19 we find IL-22 and IL-13 dichotomously induce goblet cells, in which only IL-13 driven goblet cells are 20 associated with NOTCH signaling. We further show that IL-13 induces BMP signalling to act as a 21 negative feedback loop in IL-13 induced tuft cell hyperplasia, an important aspect of type 2 immunity. 22Together, we show that targeting developmental pathways may be a useful tool to tailor epithelial 23 effector responses that are necessary for immunity to infection. 24 1 Infections of the gastrointestinal tract remain one of the leading health issues worldwide (Kirk et al. 2015). The 26 ability to clear infections relies on the capacity of the immune system to mount an appropriate response. Immune 27 responses can be divided into 3 types. Broadly; type 1 responses are launched against intracellular pathogens 28 such as bacteria and viruses and are associated with the cytokine interferon gamma (IFNγ), type 2 responses are 29 generated to fight off parasitic infections and are driven by interleukin (IL)-4 and IL-13, and finally, type 3 responses 30 are mounted against extracellular pathogens such as bacteria and are associated with IL-22 and IL-17 (Kara et al. 31 2014; Raphael et al. 2015). 32 In addition to defining the immune landscape, cytokines directly affect intestinal epithelial cells (IECs) to drive 33 immune-type specific effector responses (Biton et al. 2018). The intestinal epithelium consists of a single layer of 34 cells and is responsible both for taking up nutrients as well as providing a protective barrier. One of the hallmarks 35 of IECs is their rapid turnover (3-5 days), which allows for prompt cellular responses, for example, to expand goblet 36 cells which can produce protective mucus. This plasticity of IECs makes them particularly well-suited to defend 37 against pathogens (Tetteh, Farin, and Clevers 2015). In addition to responding to immune cues, the epithelium 38 can also be involved in tailoring immune responses. For example, tuft cells, which are important for defending 39 against parasitic helminths, are the main source of IL-25 to control ILC2 populations both in homeostasis and upon 40 helminth infection (Gerbe et al. 2016; Howitt et al. 2016; Moltke et al. 2016). As tuft cells rapidly expand upon 41 exposure to type 2 cytokines, they exemplify both how th...

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Section: Discussionmentioning

confidence: 99%

Developmental pathways regulate cytokine-driven effector and feedback responses in the intestinal epithelium

Lindholm

Parmar

Drurey

et al. 2020

Preprint

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“…1C). Interestingly, in advanced colon cancer, Tgfβ secreted by surrounding mesenchymal cells initiates a Wnt-independency in colon cancer cells 20 . To assess the role of Tgfβ on healthy small intestinal epithelium, we treated intestinal organoids using the same setup as for Bmps.…”

Section: Resultsmentioning

confidence: 99%

Terminal differentiation of villus-tip enterocytes is governed by distinct members of Tgfβ superfamily

Valenta

Berková

Fazilaty

et al. 2022

Preprint

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The protective and absorptive functions of the intestinal epithelium rely on differentiated enterocytes. Their differentiation is orchestrated by sub-epithelial mesenchymal cells producing ligands along the villus axis, in particular Bmps and Tgfβ. Here we show that individual Bmp ligands and Tgfβ drive distinct enterocytic programs specific to villus zonation. Bmp4 is expressed mainly from the center to the upper part of the villus, and it activates preferentially genes connected to lipid uptake and metabolism. In contrast, Bmp2 is produced by villus-tip mesenchymal cells, and it influences the adhesive properties of villus-tip epithelial cells and the expression of immunomodulators. Hence, Bmp2 promotes the terminal enterocytic differentiation at the villus-tip. Additionally, Tgfβ induces epithelial gene expression programs similar to that triggered by Bmp2. Bmp2-driven villus-tip program is activated by a canonical BmpRI/Smad-dependent mechanism. Finally, we established an organoid cultivation system that enriches for villus-tip enterocytes and thereby better mimics the cellular composition of the intestinal epithelium. Altogether our data suggest that not only Bmp gradient, but also the activity of individual Bmp drives specific enterocytic programs.

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Spheroids and organoids derived from colorectal cancer as tools for in vitro drug screening

Ahmad Zawawi,

Salleh,

Musa

2024

Exploration of Targeted Anti-Tumor Therapy

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Colorectal cancer (CRC) is a heterogeneous disease. Conventional two-dimensional (2D) culture employing cell lines was developed to study the molecular properties of CRC in vitro. Although these cell lines which are isolated from the tumor niche in which cancer develop, the translation to human model such as studying drug response is often hindered by the inability of cell lines to recapture original tumor features and the lack of heterogeneous clinical tumors represented by this 2D model, differed from in vivo condition. These limitations which may be overcome by utilizing three-dimensional (3D) culture consisting of spheroids and organoids. Over the past decade, great advancements have been made in optimizing culture method to establish spheroids and organoids of solid tumors including of CRC for multiple purposes including drug screening and establishing personalized medicine. These structures have been proven to be versatile and robust models to study CRC progression and deciphering its heterogeneity. This review will describe on advances in 3D culture technology and the application as well as the challenges of CRC-derived spheroids and organoids as a mode to screen for anticancer drugs.

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Lineage reversion drives WNT independence in intestinal cancer

Cited by 3 publications

References 65 publications

Developmental pathways regulate cytokine-driven effector and feedback responses in the intestinal epithelium

Developmental pathways regulate cytokine-driven effector and feedback responses in the intestinal epithelium

Terminal differentiation of villus-tip enterocytes is governed by distinct members of Tgfβ superfamily

Spheroids and organoids derived from colorectal cancer as tools for in vitro drug screening

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