KRASG12D and TP53R167H Cooperate to Induce Pancreatic Ductal Adenocarcinoma in Sus Scrofa Pigs

Principe, Daniel R.; Overgaard, Nana Haahr; Park, Alex; Diaz, Andrew M.; Torres, Carolina; McKinney, Ronald; Dorman, Matthew J.; Castellanos, Karla J.; Schwind, Regina M.; Dawson, David W.; Rana, Ajay; Maker, Ajay V.; Munshi, Hidayatullah G.; Rund, Laurie A.; Grippo, Paul J.; Schook, Lawrence B.

doi:10.1101/358416

Cited by 2 publications

(1 citation statement)

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“…Porcine tumor sections were also extensively stained positive with Masson's trichrome (Additional file 1: Fig. S8c), indicating that a desmoplastic tumor stroma developed similar to human patients with PDAC [42]. IHC staining of pancreatic head and tumor sections showed that pERK (a KRAS activation effector), PCNA (a proliferative marker), CK19 (a ductal origin marker), E-cadherin (an epithelial lineage marker), and vimentin (a mesenchymal marker) were expressed in the tumor stroma (Fig.…”

Section: Validation Of the Effectiveness Of In Vivo Genome Editing An...mentioning

confidence: 90%

Doxycycline-dependent Cas9-expressing pig resources for conditional in vivo gene nullification and activation

et al. 2023

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Background CRISPR-based toolkits have dramatically increased the ease of genome and epigenome editing. SpCas9 is the most widely used nuclease. However, the difficulty of delivering SpCas9 and inability to modulate its expression in vivo hinder its widespread adoption in large animals. Results Here, to circumvent these obstacles, a doxycycline-inducible SpCas9-expressing (DIC) pig model was generated by precise knock-in of the binary tetracycline-inducible expression elements into the Rosa26 and Hipp11 loci, respectively. With this pig model, in vivo and/or in vitro genome and epigenome editing could be easily realized. On the basis of the DIC system, a convenient Cas9-based conditional knockout strategy was devised through controlling the expression of rtTA component by tissue-specific promoter, which allows the one-step generation of germline-inherited pigs enabling in vivo spatiotemporal control of gene function under simple chemical induction. To validate the feasibility of in vivo gene mutation with DIC pigs, primary and metastatic pancreatic ductal adenocarcinoma was developed by delivering a single AAV6 vector containing TP53-sgRNA, LKB1-sgRNA, and mutant human KRAS gene into the adult pancreases. Conclusions Together, these results suggest that DIC pig resources will provide a powerful tool for conditional in vivo genome and epigenome modification for fundamental and applied research.

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Section: Validation Of the Effectiveness Of In Vivo Genome Editing An...mentioning

confidence: 90%

Doxycycline-dependent Cas9-expressing pig resources for conditional in vivo gene nullification and activation

et al. 2023

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Induction of pancreatic neoplasia in theKRAS/TP53Oncopig

Patel

Bailey

Lazenby

et al. 2020

Preprint

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Introduction.Five-year survival (all patients) from pancreatic cancer (PC) is in the range of 10%, and has not changed substantially in decades. Current murine models may not adequately mimic human PC, and can be inadequate for device development, which all may contribute to the lack of progress in PC survival. We attempted PC induction in transgenic swine (expressing KRAS and TP53 mutants) with the ultimate goal of creating a more accurate model of PC.Methods. Transgenic Oncopigs (n = 16, malensrrc.missouri.edu; somatic LSL cassette with TP53 R167H and KRAS G12D ) were injected via laparotomy with AdCre (10 10 vp/mL) ± IL-8 (0.5-2 ng; a tumor induction adjunct facilitating adenoviral entry into epithelia and promoting local inflammation) into the main pancreatic duct (MPD; via duodenotomy) or duct to the isolated pancreatic connecting lobe (CL). Subjects were necropsied after ≤10 wk, followed by histology.

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KRAS^G12D and TP53^R167H Cooperate to Induce Pancreatic Ductal Adenocarcinoma in Sus Scrofa Pigs

Cited by 2 publications

References 30 publications

Doxycycline-dependent Cas9-expressing pig resources for conditional in vivo gene nullification and activation

Doxycycline-dependent Cas9-expressing pig resources for conditional in vivo gene nullification and activation

Induction of pancreatic neoplasia in theKRAS/TP53Oncopig

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