A surgical orthotopic organoid transplantation approach in mice to visualize and study colorectal cancer progression

Fumagalli, Arianna; Suijkerbuijk, Saskia J.E.; Begthel, Harry; Beerling, Evelyne; Oost, Koen C.; Snippert, Hugo J.G.; Rheenen, Jacco van; Drost, Jarno

doi:10.1038/nprot.2017.137

Cited by 80 publications

(70 citation statements)

References 44 publications

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“…When engrafted into mice, these mutated organoids grow as invasive cancer [160]. However, they spontaneously metastasize to the lungs and liver only when orthotopically transplanted into the cecum of the animals [161,162], suggesting that advanced processes in carcinogenesis are heavily dependent on microenvironmental factors [125]. In another study, oncogenic mutations in CDKN2A, KRAS, TP53, and SMAD4 introduced into human pancreatic organoids transformed normal cells into cancer cells, modelling primary and invasive pancreatic ductal adenocarcinoma when xenotransplanted in vivo [163].…”

Section: Organoids As a Model To Study Tumorigenesismentioning

confidence: 99%

Modeling neoplastic disease with spheroids and organoids

et al. 2020

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Cancer is a complex disease in which both genetic defects and microenvironmental components contribute to the development, progression, and metastasization of disease, representing major hurdles in the identification of more effective and safer treatment regimens for patients. Three-dimensional (3D) models are changing the paradigm of preclinical cancer research as they more closely resemble the complex tissue environment and architecture found in clinical tumors than in bidimensional (2D) cell cultures. Among 3D models, spheroids and organoids represent the most versatile and promising models in that they are capable of recapitulating the heterogeneity and pathophysiology of human cancers and of filling the gap between conventional 2D in vitro testing and animal models. Such 3D systems represent a powerful tool for studying cancer biology, enabling us to model the dynamic evolution of neoplastic disease from the early stages to metastatic dissemination and the interactions with the microenvironment. Spheroids and organoids have recently been used in the field of drug discovery and personalized medicine. The combined use of 3D models could potentially improve the robustness and reliability of preclinical research data, reducing the need for animal testing and favoring their transition to clinical practice. In this review, we summarize the recent advances in the use of these 3D systems for cancer modeling, focusing on their innovative translational applications, looking at future challenges, and comparing them with most widely used animal models.

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Section: Organoids As a Model To Study Tumorigenesismentioning

confidence: 99%

Modeling neoplastic disease with spheroids and organoids

et al. 2020

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“…Colon orthotopic transplantation and metastasis analysis. Colon orthotopic transplantation of CT26 cells (CT26-shControl and CT26-KRS-suppressed cells: CT26-shKRS#2 and CT26-shKRS#5) was performed as explained previously (27). Both CT26 cell lines were first stably infected with retroviral pMSCV-Luc2 vector (37), and then injected s.c. into BALB/c-nude (female, 6-week-old; Orient Bio) mice.…”

Section: Methodsmentioning

confidence: 99%

Lysyl-tRNA synthetase–expressing colon spheroids induce M2 macrophage polarization to promote metastasis

Nam¹,

Kim

Lee³

et al. 2018

Journal of Clinical Investigation

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Lysyl-tRNA synthetase (KRS) functions canonically in cytosolic translational processes. However, KRS is highly expressed in colon cancer, and localizes to distinct cellular compartments upon phosphorylations (i.e., the plasma membranes after T52 phosphorylation and the nucleus after S207 phosphorylation), leading to probably alternative noncanonical functions. It is unknown how other subcellular KRSs crosstalk with environmental cues during cancer progression. Here, we demonstrate that the KRS-dependent metastatic behavior of colon cancer spheroids within 3D gels requires communication between cellular molecules and extracellular soluble factors and neighboring cells. Membranous KRS and nuclear KRS were found to participate in invasive cell dissemination of colon cancer spheroids in 3D gels. Cancer spheroids secreted GAS6 via a KRS-dependent mechanism and caused the M2 polarization of macrophages, which activated the neighboring cells via secretion of FGF2/GROα/M-CSF to promote cancer dissemination under environmental remodeling via fibroblast-mediated laminin production. Analyses of tissues from clinical colon cancer patients and Krs-/+ animal models for cancer metastasis supported the roles of KRS, GAS6, and M2 macrophages in KRS-dependent positive feedback between tumors and environmental factors. Altogether, KRS in colon cancer cells remodels the microenvironment to promote metastasis, which can thus be therapeutically targeted at these bidirectional KRS-dependent communications of cancer spheroids with environmental cues.

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“…Having demonstrated the presence of EntF* in vivo as well as its in vitro effects, we evaluated its in vivo metastasis-promoting activities using an orthotopic colorectal cancer mouse model 25,26 . Before the luciferase-transfected HCT-8 cells were implanted into the wall of the caecum of the mice, cells were treated daily for five days with EntF* (100 nM), phosphate-buffered saline (PBS) vehicle or Transforming Growth Factor α (TGFα, positive control) (0.1 µg mL -1 ).…”

Section: In Vivo Pro-metastatic Properties Of Entf* In Micementioning

confidence: 99%

The Quorum Sensing Peptide EntF* Promotes Colorectal Cancer Metastasis in Mice: A New Factor in the Microbiome-Host Interaction

Debunne

Wynendaele

Janssens

et al. 2020

Preprint

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BackgroundColorectal cancer, one of the most common malignancies worldwide, is associated with a high mortality rate, mainly caused by metastasis. Comparative metagenome-wide analyses between healthy individuals and cancer patients suggest a role for the human intestinal microbiota. Nevertheless, which microbial molecules are involved in this communication is largely unknown, with current studies mainly focusing on short chain fatty acids and amino acid metabolites as potential mediators. However, quorum sensing peptides are not yet considered in this microbiome-host interaction: their in vivo presence nor any in vivo host-effect have been reported.ResultsFor the first time, we showed that a quorum sensing peptide metabolite, EntF* produced by intestinal microbiota (E. faecium), is present in the blood circulation of mice. Moreover, it significantly promotes colorectal cancer metastasis in vivo, with metastatic lesions found in both liver and lung tissues, using an orthotopic mice model evaluating bioluminescence as well as macroscopic and microscopic presence of metastatic tumour nodules. In vitro tests on E-cadherin expression levels thereby indicated that the first, second, sixth and tenth amino acid of EntF* were critical for the epithelial-mesenchymal transition (EMT) effect, responsible for tumour metastasis.ConclusionThis paper adds a new group of molecules, the quorum sensing peptides, as an additional causative factor explaining the microbiome-host interaction. The presence of a selected quorum sensing peptide (metabolite) in the mouse was proven for the first time and its in vivo effect on colorectal metastasis was demonstrated. We anticipate our in vivo results to be a starting point for broader microbiome-health investigations, not only limited to colorectal cancer metastasis, but also for developing novel bio-therapeutics in other disease areas, giving due attention to the QSP produced by the microbiome.

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A surgical orthotopic organoid transplantation approach in mice to visualize and study colorectal cancer progression

Cited by 80 publications

References 44 publications

Modeling neoplastic disease with spheroids and organoids

Modeling neoplastic disease with spheroids and organoids

Lysyl-tRNA synthetase–expressing colon spheroids induce M2 macrophage polarization to promote metastasis

The Quorum Sensing Peptide EntF* Promotes Colorectal Cancer Metastasis in Mice: A New Factor in the Microbiome-Host Interaction

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