RB inactivation in keratin 18 positive thymic epithelial cells promotes non-cell autonomous T cell hyperproliferation in genetically engineered mice

Song, Yurong; Sullivan, Teresa; Klarmann, Kimberly D.; Gilbert, Debra J.; O’Sullivan, T. Norene; Wang, Xin Wei; Haines, Diana C.; Dyke, Terry Van; Keller, Jonathan R.

doi:10.1371/journal.pone.0171510

Cited by 2 publications

(2 citation statements)

References 52 publications

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“…Tumors were removed and fixed in 10% neutral buffered formalin overnight, transferred to 70% ethanol, and then routinely processed and embedded in paraffin. Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining were carried out on 4-mm sections as previously described (26) (Supplementary Table 1). Slides were digitally imaged using an Aperio ScanScope Scanner (Leica Biosystems).…”

Section: Histopathology and Immunostainingmentioning

confidence: 99%

Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer

Song,

Kerr,

Sanders

et al. 2023

Front. Oncol.

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BackgroundGenome integrity is essential for the survival of an organism. DNA mismatch repair (MMR) genes (e.g., MLH1, MSH2, MSH6, and PMS2) play a critical role in the DNA damage response pathway for genome integrity maintenance. Germline mutations of MMR genes can lead to Lynch syndrome or constitutional mismatch repair deficiency syndrome, resulting in an increased lifetime risk of developing cancer characterized by high microsatellite instability (MSI-H) and high mutation burden. Although immunotherapy has been approved for MMR-deficient (MMRd) cancer patients, the overall response rate needs to be improved and other management options are needed.MethodsTo better understand the biology of MMRd cancers, elucidate the resistance mechanisms to immune modulation, and develop vaccines and therapeutic testing platforms for this high-risk population, we generated organoids and an orthotopic mouse model from intestine tumors developed in a Msh2-deficient mouse model, and followed with a detailed characterization.ResultsThe organoids were shown to be of epithelial origin with stem cell features, to have a high frameshift mutation frequency with MSI-H and chromosome instability, and intra- and inter-tumor heterogeneity. An orthotopic model using intra-cecal implantation of tumor fragments derived from organoids showed progressive tumor growth, resulting in the development of adenocarcinomas mixed with mucinous features and distant metastasis in liver and lymph node.ConclusionsThe established organoids with characteristics of MSI-H cancers can be used to study MMRd cancer biology. The orthotopic model, with its distant metastasis and expressing frameshift peptides, is suitable for evaluating the efficacy of neoantigen-based vaccines or anticancer drugs in combination with other therapies.

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Section: Histopathology and Immunostainingmentioning

confidence: 99%

Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer

Song,

Kerr,

Sanders

et al. 2023

Front. Oncol.

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“…Cell pellets or tumor tissues were fixed in 10% neutral-buffered formalin (NBF), and formalin-fixed paraffin-embedded (FFPE) blocks were made and sectioned for Hematoxylin and Eosin (H&E) and immunohistochemistry (IHC) staining, as described previously [36]. The antibodies used are listed in Table S1.…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

Mesothelioma Mouse Models with Mixed Genomic States of Chromosome and Microsatellite Instability

Baxter

Dai

Sanders

et al. 2022

Cancers

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Malignant mesothelioma (MMe) is a rare malignancy originating from the linings of the pleural, peritoneal and pericardial cavities. The best-defined risk factor is exposure to carcinogenic mineral fibers (e.g., asbestos). Genomic studies have revealed that the most frequent genetic lesions in human MMe are mutations in tumor suppressor genes. Several genetically engineered mouse models have been generated by introducing the same genetic lesions found in human MMe. However, most of these models require specialized breeding facilities and long-term exposure of mice to asbestos for MMe development. Thus, an alternative model with high tumor penetrance without asbestos is urgently needed. We characterized an orthotopic model using MMe cells derived from Cdkn2a+/−;Nf2+/− mice chronically injected with asbestos. These MMe cells were tumorigenic upon intraperitoneal injection. Moreover, MMe cells showed mixed chromosome and microsatellite instability, supporting the notion that genomic instability is relevant in MMe pathogenesis. In addition, microsatellite markers were detectable in the plasma of tumor-bearing mice, indicating a potential use for early cancer detection and monitoring the effects of interventions. This orthotopic model with rapid development of MMe without asbestos exposure represents genomic instability and specific molecular targets for therapeutic or preventive interventions to enable preclinical proof of concept for the intervention in an immunocompetent setting.

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RB inactivation in keratin 18 positive thymic epithelial cells promotes non-cell autonomous T cell hyperproliferation in genetically engineered mice

Cited by 2 publications

References 52 publications

Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer

Organoids and metastatic orthotopic mouse model for mismatch repair-deficient colorectal cancer

Mesothelioma Mouse Models with Mixed Genomic States of Chromosome and Microsatellite Instability

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