Induction and characterization of pancreatic cancer in a transgenic pig model

Boas, F. Edward; Nurili, Fuad; Bendet, Achiude; Cheleuitte-Nieves, Christopher; Baştürk, Olca; Aşkan, Gökçe; Michel, Adam O.; Monette, Sébastien; Ziv, Etay; Sofocleous, Constantinos T.; Maxwell, Aaron W.P.; Schook, Lawrence B.; Solomon, Stephen B.; Kelsen, David P.; Scherz, Avigdor; Yarmohammadi, Hooman

doi:10.1371/journal.pone.0239391

Cited by 24 publications

(15 citation statements)

References 36 publications

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“…Hence, in the absence of IFNg-producing T-cells, the disruption of TGFb/SMAD signals appears to enhance PD-L1 expression similar to what was observed in cell culture. Therefore, this study affirms the need to both refine mouse models of PDAC and to incorporate complementary model systems when studying immuno-oncology such as ex vivo slice cultures, patient-derived xenografts in partially humanized mice, and large animal models of PDAC (45)(46)(47)(48)(49).…”

Section: Discussionsupporting

confidence: 62%

Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer

et al. 2022

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Transforming Growth Factor β (TGFβ) is a key mediator of immune evasion in pancreatic ductal adenocarcinoma (PDAC), and the addition of TGFβ inhibitors in select immunotherapy regimens shows early promise. Though the TGFβ target SMAD4 is deleted in approximately 55% of PDAC tumors, the effects of SMAD4 loss on tumor immunity have yet to be fully explored. Using a combination of genomic databases and PDAC specimens, we found that tumors with loss of SMAD4 have a comparatively poor T-cell infiltrate. SMAD4 loss was also associated with a reduction in several chemokines with known roles in T-cell recruitment, which was recapitulated using knockdown of SMAD4 in PDAC cell lines. Accordingly, JURKAT T-cells were poorly attracted to conditioned media from PDAC cells with knockdown of SMAD4 and lost their ability to produce IFNγ. However, while exogenous TGFβ modestly reduced PD-L1 expression in SMAD4-intact cell lines, SMAD4 and PD-L1 positively correlated in human PDAC samples. PD-L1 status was closely related to tumor-infiltrating lymphocytes, particularly IFNγ-producing T-cells, which were more abundant in SMAD4-expressing tumors. Low concentrations of IFNγ upregulated PD-L1 in tumor cells in vitro, even when administered alongside high concentrations of TGFβ. Hence, while SMAD4 may have a modest inhibitory effect on PD-L1 in tumor cells, SMAD4 indirectly promotes PD-L1 expression in the pancreatic tumor microenvironment by enhancing T-cell infiltration and IFNγ biosynthesis. These data suggest that pancreatic cancers with loss of SMAD4 represent a poorly immunogenic disease subtype, and SMAD4 status warrants further exploration as a predictive biomarker for cancer immunotherapy.

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Section: Discussionsupporting

confidence: 62%

Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer

et al. 2022

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“…Since Wilmut et al obtained the world's first somatic cell cloned sheep Dolly in 1997 (Colman, 1999; Wilmut et al., 1997), SCNT has quickly become the most widely used technology in the production of transgenic animals (Boas et al., 2020; Liu et al., 2018; Song et al., 2016; Yang et al., 2017; Zhang et al., 2019). However, the key to the production of transgenic animals by SCNT is the selection of donor cells.…”

Section: Discussionmentioning

confidence: 99%

Developmental analysis of reconstructed embryos of second‐generation cloned transgenic goats

Song

Lü

Cheng

et al. 2022

Reprod Domestic Animals

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To improve the efficiency of the production of transgenic cloned goats by somatic cell nuclear transfer (SCNT), the development of reconstructed embryos of firstgeneration (G1) and second-generation (G2) cloned transgenic goats was compared and analysed. Primary transgenic foetal fibroblasts were used as donor cells for G1 somatic cell nuclear transfer (SCNT). When the G1 transgenic embryos developed to 35 days in the recipient goats, transgenic foetal fibroblasts were isolated from them and used as donor cells for the G2 clone. In the G1 clones, the average fusion rate of reconstructed embryos was 73.62 ± 2.9%, the average development rate(2-4 cells) was 33.96 ± 2.36%, and the pregnancy rate of transplant recipients was 31.91%. In the G2 clones, the average fusion rate of the reconstructed embryos was 90.29 ± 2.03%, the average development rate was 66.46 ± 3.30%, and the pregnancy rate was 58.14%. These results indicate that in the G2 clones, the fusion rate of eggs, the development rate of reconstructed embryos and the pregnancy rate of transplant recipients were significantly higher than those of G1 clones. We believe these results will lay a solid foundation for the efficient production of transgenic cloned animals in the future.

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“…There are alternative approaches for a orthotopic porcine model of PDAC. The Oncopig 31 can generate PDAC 103 , 106 , 107 in vivo, but this model contains a somatic LSL-cassette that is present in every cell, so off-target transformation is possible. This off-target effect can result in transformation of multiple cell types and pleomorphic tumors 107 .…”

Section: Discussionmentioning

confidence: 99%

Porcine pancreatic ductal epithelial cells transformed with KRASG12D and SV40T are tumorigenic

Bailey

Cartwright

Patel

et al. 2021

Sci Rep

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We describe our initial studies in the development of an orthotopic, genetically defined, large animal model of pancreatic cancer. Primary pancreatic epithelial cells were isolated from pancreatic duct of domestic pigs. A transformed cell line was generated from these primary cells with oncogenic KRAS and SV40T. The transformed cell lines outperformed the primary and SV40T immortalized cells in terms of proliferation, population doubling time, soft agar growth, transwell migration and invasion. The transformed cell line grew tumors when injected subcutaneously in nude mice, forming glandular structures and staining for epithelial markers. Future work will include implantation studies of these tumorigenic porcine pancreatic cell lines into the pancreas of allogeneic and autologous pigs. The resultant large animal model of pancreatic cancer could be utilized for preclinical research on diagnostic, interventional, and therapeutic technologies.

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Induction and characterization of pancreatic cancer in a transgenic pig model

Cited by 24 publications

References 36 publications

Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer

Loss of SMAD4 Is Associated With Poor Tumor Immunogenicity and Reduced PD-L1 Expression in Pancreatic Cancer

Developmental analysis of reconstructed embryos of second‐generation cloned transgenic goats

Porcine pancreatic ductal epithelial cells transformed with KRASG12D and SV40T are tumorigenic

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