Establishment of gastrointestinal assembloids to study the interplay between epithelial crypts and their mesenchymal niche

Lin, Manqiang; Hartl, Kimberly; Heuberger, Julian; Beccaceci, Giulia; Berger, Hilmar; Li, Hao; Liu, Lichao; Müllerke, Stefanie; Conrad, Thomas; Heymann, Felix; Woehler, Andrew; Tacke, Frank; Rajewsky, Nikolaus; Sigal, Michael

doi:10.1038/s41467-023-38780-3

Cited by 13 publications

(8 citation statements)

References 56 publications

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“…We observed that CAFs support the survival and proliferation of EAC PDOs in complete DMEM, crucially enabling low-cost model production and scalability. This was also observed in PDAC 23 , normal colon 34 and CRC 24 where growth of the epithelial compartment was supplemented by fibroblasts even in the absence of exogenous Wnt and BMP signaling activators. We observed spatial arrangements of EAC assembloid models comparable to those seen in multicellular tumor spheroids, where reduced access to oxygen and nutrients internally causes models to proliferate in peripheral areas, with central quiescence and necrosis as spheroids grow larger 36 .…”

Section: Discussionmentioning

confidence: 63%

Patient-Derived Tumor Organoid and Fibroblast Assembloid Models for interrogation of the tumor microenvironment in Esophageal Adenocarcinoma

Sharpe,

Nazlamova,

Tse

et al. 2024

Preprint

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The tumor microenvironment (TME) comprises all non-tumor elements of cancer and strongly influences disease progression and phenotype. To understand tumor biology and accurately test new therapeutic strategies, representative models should contain both tumor cells and normal cells of the TME. Here we describe and characterize co-culture tumor-derived organoids and cancer-associated fibroblasts (CAFs), a major component of the TME, in matrix-embedded assembloid models of esophageal adenocarcinoma (EAC). We demonstrate that the assembloid models faithfully recapitulate the differentiation status of EAC and different CAF phenotypes found in the EAC patient TME. We evaluate cell phenotypes by combining tissue clearing techniques with wholemount immunofluorescence and histology, providing a practical framework for characterization of cancer assembloids.

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Section: Discussionmentioning

confidence: 63%

Patient-Derived Tumor Organoid and Fibroblast Assembloid Models for interrogation of the tumor microenvironment in Esophageal Adenocarcinoma

Sharpe,

Nazlamova,

Tse

et al. 2024

Preprint

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“…This system also presented stem/progenitor cells able to differentiate into secretory/absorptive cells. As well as Kim et al (2020) highlighted the role of BMPs in bladder tumors, the data obtained by Lin et al (2023) indicated the importance of stromal BMP signaling for gastrointestinal and colonic homeostasis. Indeed, assembloids from wild-type stromal cells and BMP receptor type 1A (BMPR1A) knock-out were generated, but those knock-out for BMPR1A failed to compartmentalize remaining as spheroids, and epithelial cells did not differentiate; this confirmed the pivotal role of BMP signaling for epithelial differentiation and crypt formation.…”

Section: Assembloids: a New Powerful Tool For Disease Modeling And Dr...mentioning

confidence: 95%

“…As a result, it emerged that stromal bone morphogenetic proteins (BMPs) induced tumoral FOXA1 expression and this, in turn, directs the tumor towards a specific phenotype. Another example in literature is provided by Lin et al (2023), who investigated the interplay between epithelial crypts and their mesenchymal niche using a colon assembloid system, formed by the epithelium and different stromal cell subtypes, recapitulating mature crypts. This system also presented stem/progenitor cells able to differentiate into secretory/absorptive cells.…”

Section: Assembloids: a New Powerful Tool For Disease Modeling And Dr...mentioning

confidence: 99%

iPSCs as a groundbreaking tool for the study of adverse drug reactions: A new avenue for personalized therapy

Rispoli,

Scandiuzzi Piovesan,

Decorti

et al. 2023

WIREs Mechanisms of Disease

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Induced pluripotent stem cells (iPSCs), obtained by reprogramming different somatic cell types, represent a promising tool for the study of drug toxicities, especially in the context of personalized medicine. Indeed, these cells retain the same genetic heritage of the donor, allowing the development of personalized models. In addition, they represent a useful tool for the study of adverse drug reactions (ADRs) in special populations, such as pediatric patients, which are often poorly represented in clinical trials due to ethical issues. Particularly, iPSCs can be differentiated into any tissue of the human body, following several protocols which use different stimuli to induce specific differentiation processes. Differentiated cells also maintain the genetic heritage of the donor, and therefore are suitable for personalized pharmacological studies; moreover, iPSC‐derived differentiated cells are a valuable tool for the investigation of the mechanisms underlying the physiological differentiation processes. iPSCs‐derived organoids represent another important tool for the study of ADRs. Precisely, organoids are in vitro 3D models which better represent the native organ, both from a structural and a functional point of view. Moreover, in the same way as iPSC‐derived 2D models, iPSC‐derived organoids are appropriate personalized models since they retain the genetic heritage of the donor. In comparison to other in vitro models, iPSC‐derived organoids present advantages in terms of versatility, patient‐specificity, and ethical issues. This review aims to provide an updated report of the employment of iPSCs, and 2D and 3D models derived from these, for the study of ADRs.This article is categorized under: Cancer > Stem Cells and Development

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Section: Organoid and Assembloid Technologymentioning

confidence: 99%

“…Assembloid technology, owing to its enhanced structural organization, has been swiftly integrated into domains, such as tissue remodelling, 40 tissue spatial genomics 41,42 and drug delivery assessment, 43 among others. Similarly, assembloid technology has found applications in normal tissues, including the brain 44 and the gastrointestinal tract, 40 as well as cancers, such as bladder cancer 37 and small‐cell lung cancer 45 . Many bioengineering tools have been proposed to facilitate assembloid fabrications, such as human brain assembloids using microfluidics, 44 and spatially constructing glioma organoids using 3D bioprinting 46 .…”

Section: Organoid and Assembloid Technologymentioning

confidence: 99%

Tumour organoids and assembloids: Patient‐derived cancer avatars for immunotherapy

Mei,

Liu,

Tian

et al. 2024

Clinical & Translational Med

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BackgroundOrganoid technology is an emerging and rapidly growing field that shows promise in studying organ development and screening therapeutic regimens. Although organoids have been proposed for a decade, concerns exist, including batch‐to‐batch variations, lack of the native microenvironment and clinical applicability.Main bodyThe concept of organoids has derived patient‐derived tumour organoids (PDTOs) for personalized drug screening and new drug discovery, mitigating the risks of medication misuse. The greater the similarity between the PDTOs and the primary tumours, the more influential the model will be. Recently, ‘tumour assembloids’ inspired by cell‐coculture technology have attracted attention to complement the current PDTO technology. High‐quality PDTOs must reassemble critical components, including multiple cell types, tumour matrix, paracrine factors, angiogenesis and microorganisms. This review begins with a brief overview of the history of organoids and PDTOs, followed by the current approaches for generating PDTOs and tumour assembloids. Personalized drug screening has been practised; however, it remains unclear whether PDTOs can predict immunotherapies, including immune drugs (e.g. immune checkpoint inhibitors) and immune cells (e.g. tumour‐infiltrating lymphocyte, T cell receptor‐engineered T cell and chimeric antigen receptor‐T cell). PDTOs, as cancer avatars of the patients, can be expanded and stored to form a biobank.ConclusionFundamental research and clinical trials are ongoing, and the intention is to use these models to replace animals. Pre‐clinical immunotherapy screening using PDTOs will be beneficial to cancer patients.Key Points The current PDTO models have not yet constructed key cellular and non‐cellular components. PDTOs should be expandable and editable. PDTOs are promising preclinical models for immunotherapy unless mature PDTOs can be established. PDTO biobanks with consensual standards are urgently needed.

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Establishment of gastrointestinal assembloids to study the interplay between epithelial crypts and their mesenchymal niche

Cited by 13 publications

References 56 publications

Patient-Derived Tumor Organoid and Fibroblast Assembloid Models for interrogation of the tumor microenvironment in Esophageal Adenocarcinoma

Patient-Derived Tumor Organoid and Fibroblast Assembloid Models for interrogation of the tumor microenvironment in Esophageal Adenocarcinoma

iPSCs as a groundbreaking tool for the study of adverse drug reactions: A new avenue for personalized therapy

Tumour organoids and assembloids: Patient‐derived cancer avatars for immunotherapy

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