Challenges in genomic analysis of model systems and primary tumors of pancreatic ductal adenocarcinoma

Hyun, Sangyeop; Park, Daechan

doi:10.1016/j.csbj.2022.08.064

Cited by 5 publications

(4 citation statements)

References 73 publications

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“…The interaction between tumour cells and the TME undoubtedly plays an important role in supporting tumour growth, progression, and response to treatment 15,16,18 . However, experimental limitations including difficulty accessing tumour samples with sufficient cellularity for analysis and a lack of disease-representative in vitro models have hindered explorations of the specific impacts of microenvironmental features on transcriptional phenotypes in PDAC 59,65,66 . Although scRNA-seq has offered deeper insight into the transcriptional heterogeneity of tumour cells, it has not been possible to correlate transcriptional phenotypes with the tumour cell-extrinsic features of a defined location in the TME.…”

Section: Discussionmentioning

confidence: 99%

Single-cell analysis of an engineered organoid-based model of pancreatic cancer identifies hypoxia as a contributing factor in the determination of transcriptional subtypes

Landon-Brace,

Innes,

Latour

et al. 2024

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is a high-mortality cancer characterized by its aggressive, treatment-resistant phenotype and a complex tumour microenvironment (TME) featuring significant hypoxia. Bulk transcriptomic analysis has identified the classical and basal-like transcriptional subtypes which have prognostic value in PDAC; however, it remains unclear how microenvironmental heterogeneity contributes to the expression of these transcriptional signatures. Here, we used single cell transcriptome analysis of the organoid TRACER platform to explore the effect of oxygen and other microenvironmental gradients on PDAC organoid cells. We found that the microenvironmental gradients present in TRACER significantly impact the distribution of organoid transcriptional phenotypes and the enrichment of gene sets linked to cancer progression and treatment resistance. More significantly, we found that microenvironmental gradients drive changes in the expression of the classical and basal-like transcriptional subtype gene signatures. This effect is likely dominated by the oxygen gradients in TRACER, as hypoxia alone induced decreases in the expression of classical marker GATA6 at both the gene and protein level in PDAC cells. This work suggests that hypoxia contributes to determining transcriptional subtypes in PDAC and broadly underscores the importance of considering microenvironmental gradients in organoid-based transcriptomic studies of PDAC.

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Section: Discussionmentioning

confidence: 99%

Single-cell analysis of an engineered organoid-based model of pancreatic cancer identifies hypoxia as a contributing factor in the determination of transcriptional subtypes

Landon-Brace,

Innes,

Latour

et al. 2024

Preprint

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“…Our PDX panel reflects the heterogeneous pheno-and genotype of PC and can contribute to identifying biomarkers for tumor progression and therapy response at an experimental stage. When working with PDX, everyone should keep the limits of these models in mind [66,93]: maintenance of human tumor tissues in mice selects the fast adapting population of cancer cells, altering the clonal heterogeneity of the PDX tumor, while the influential human tumor stroma is replaced by murine analogues and the tumor-intrinsic immune cells are lost. However, no other preclinical model provides this high heterogeneity of tumor cells and similarity of morphologic and genomic features with patient material [29,37].…”

Section: Discussionmentioning

confidence: 99%

Establishment and Thorough Characterization of Xenograft (PDX) Models Derived from Patients with Pancreatic Cancer for Molecular Analyses and Chemosensitivity Testing

Behrens,

Pfohl,

Conrad

et al. 2023

Cancers

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Patient-derived xenograft (PDX) tumor models are essential for identifying new biomarkers, signaling pathways and novel targets, to better define key factors of therapy response and resistance mechanisms. Therefore, this study aimed at establishing pancreas carcinoma (PC) PDX models with thorough molecular characterization, and the identification of signatures defining responsiveness toward drug treatment. In total, 45 PC-PDXs were generated from 120 patient tumor specimens and the identity of PDX and corresponding patient tumors was validated. The majority of engrafted PDX models represent ductal adenocarcinomas (PDAC). The PDX growth characteristics were assessed, with great variations in doubling times (4 to 32 days). The mutational analyses revealed an individual mutational profile of the PDXs, predominantly showing alterations in the genes encoding KRAS, TP53, FAT1, KMT2D, MUC4, RNF213, ATR, MUC16, GNAS, RANBP2 and CDKN2A. Sensitivity of PDX toward standard of care (SoC) drugs gemcitabine, 5-fluorouracil, oxaliplatin and abraxane, and combinations thereof, revealed PDX models with sensitivity and resistance toward these treatments. We performed correlation analyses of drug sensitivity of these PDX models and their molecular profile to identify signatures for response and resistance. This study strongly supports the importance and value of PDX models for improvement in therapies of PC.

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“…Tissues from the patient can be stored as fragments or processed to generate uniform 200-300 mm sections in the culturing media. 50 Many other improved methods have also been applied to the establishment of PDEs. (Fig.…”

Section: Patient-derived Explantsmentioning

confidence: 99%

Pancreatic cancer environment: from patient-derived models to single-cell omics

Gu,

Li,

Qiu

et al. 2024

Mol. Omics

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Challenges in genomic analysis of model systems and primary tumors of pancreatic ductal adenocarcinoma

Cited by 5 publications

References 73 publications

Single-cell analysis of an engineered organoid-based model of pancreatic cancer identifies hypoxia as a contributing factor in the determination of transcriptional subtypes

Single-cell analysis of an engineered organoid-based model of pancreatic cancer identifies hypoxia as a contributing factor in the determination of transcriptional subtypes

Establishment and Thorough Characterization of Xenograft (PDX) Models Derived from Patients with Pancreatic Cancer for Molecular Analyses and Chemosensitivity Testing

Pancreatic cancer environment: from patient-derived models to single-cell omics

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