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An organoid-based transplantation model reveals genetic interactions potentiating niche-independent gastric carcinogenesis

ABSTRACT: Despite distinct genetic aberrations introduced and diverse tumor histology, the derived tumor-derived organoids stereotypically exhibited cystic features. To clarify distinct genotype-dependent properties of p53-null tumor-derived organoids, seven tumor-derived organoids and organoids with pLKO.1 and shLuc were compared.

ORGANISM(S): Mus musculus

PROVIDER: GSE192604 | GEO | 2022/12/31

REPOSITORIES: GEO

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality among adults in developed countries. The discovery of the most common genetic alterations as well as the development of organoids models of pancreatic cancer have provided insight into the fundamental pathways driving the progression from normal cell, to non-invasive precursor lesion, to widely metastatic disease, offering new opportunities for the discovery of key activated pathways along cancer progression. Obesity is one of the most serious public health challenges of the 21st century. Several epidemiological studies have shown the positive association between obesity and cancer-related morbidity/mortality, as well as poor prognosis and poorer treatment outcome. Despite strong evidence indicates a link between obesity and cancer incidence, the molecular basis of the initiating events remains largely elusive. This is mainly due to the lack of an accurate and reliable model of pancreatic carcinogenesis that mimics human obesity-associated PDAC, making data interpretation difficult and often confusing. Here we propose, to our knowledge, the best suitable and manageable preclinical tool, based on next-generation cell culture models, to study the effects of obesity on pancreatic carcinogenesis. Therefore we tracked the effects of obesity on the natural evolution of PDAC in a genetically-defined transplantable model of syngeneic murine pancreatic preneoplastic lesion (mP) and tumor (mT) derived organoids that recapitulates the progression of human disease from early preinvasive lesions to metastatic disease. Our models indicated that both genetic- and diet-induced obesity promoted incidence engraftment rate and growth of both preneoplastic and neoplastic organoids, favoring pancreatic cancer progression and distant metastases dissemination. Our obesity models of carcinogenesis mimic the evolution of human pancreatic cancer pathology, promoting carcinogenesis and concomitant accumulation of a myeloid infiltrate. These changes in cancer immune infiltrate were also associated to a specific pattern of anti-inflammatory Th2 signature. Moreover, gene expression profile analysis revealed a change in gene expression programs that addresses cells to different pancreatic subtypes and stromal conditions. Our results suggest that organoid-derived transplants in obese mice represent a suitable system to study early step of carcinogenesis and support the hypothesis that inflammation induced by obesity stimulates tumor progression and metastatization during pancreatic carcinogenesis.

Project description:Purpose: Transcriptome profiling of organoids/tissues derived from murine oviduct and OSE was performed to study and compare the gene expression profiles in the both suspected origins of HG-SOC. CRISPR-Cas9 modified oviductal organoids (TBP clones, which were mutated in Trp53, Brca1 and Pten), the tumors derived upon xenotransplantation of the TBP-clones and subsequent tumor-derived organoids were additionally profiled to show the transcriptional change upon aquiring mutations and tumor development. Methods: Both oviductal and OSE organoids as well as oviductal TBP-clones and tumor-derived organoids were grown in Wnt-conditioned media prior harvesting for RNA extraction. Additionally, RNA was extracted from healthy oviductal and OSE tissues and Ovi-TBP-clone-derived tumor tissues. RNA was converted to cDNA and libraries were prepared using the CelSeq2 method and sequenced. Samples were sequenced on Illumina NextSeq500 by using 75-bp paired-end sequencing. Paired-end reads from Illumina sequencing were aligned to the mouse genome (GRCm38 assembly) by BWA. DESeq2 (v1.18.0) package was used for read normalization and differential expression analysis. Gene set enrichment analysis (GSEA) was performed using gene lists for motile cilium assembly against normalized RNA-seq reads of healthy oviductal an OSE organoids using GSEA software v3.0 beta2. GSEA was additionally used to detect enrichment of signature gene sets of different HG-SOC subtypes in the TBP-clone-derived murine tumors Results: Transcriptome analysis of oviductal and OSE organoids/tissues revealed tissue-specific gene expression pattern in the organoid systems. In contrast to OSE counterparts, oviductal organoids showed enrichment in motile cilium assembly genes, reflecting the presence of ciliated cells in this model. Results: Oviductal TBP-clones gave rise to different tumor phenotypes with distinct gene expression profiles. Analysis of the transcriptomes of these tumors divided the TBP-clone-derived tumors into two distinct HG-SOC molecular subtypes (differentiated- or immunoreactive-like subtypes), confirming the potential of organoids in modeling HG-SOC. Results: The tumor-derived organoids retained the distinct phenotypes observed in the originating Ovi-TBP-clone derived tumors. Subset of tumors showed epithelial and others mesenchymal features that were maintained in the respective organoid cultures also in the gene expression level. Conclusions: RNA sequencing showed tissue specific differences in murine oviductal and OSE organoids, and revealed HG-SOC-like features of oviductal mutants.

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An organoid-based transplantation model reveals genetic interactions potentiating niche-independent gastric carcinogenesis

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