Establishing an immunocompromised porcine model of human cancer for novel therapy development with pancreatic adenocarcinoma and irreversible electroporation

Alissa Hendricks-Wenger,Natalie Beitel-White,Melvin F Lorenzo,Holly A Morrison,Irving C Allen,Sheryl Coutermarsh-Ott,Kayla Farrell,Kiho Lee,Joanne Tuohy,Alexander Simon,Rafael V Davalos,Kenneth N Aycock,Margaret A Nagai-Singer,Jessica Gannon,Rebecca M Brock,Kyungjun Uh,Sherrie Clark-Deener,Eli Vlaisavljevich

doi:10.1038/s41598-021-87228-5

Alissa Hendricks-Wenger, Natalie Beitel-White + Show 16 more

Open Access

https://doi.org/10.1038/s41598-021-87228-5

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Abstract

New therapies to treat pancreatic cancer are direly needed. However, efficacious interventions lack a strong preclinical model that can recapitulate patients’ anatomy and physiology. Likewise, the availability of human primary malignant tissue for ex vivo studies is limited. These are significant limitations in the biomedical device field. We have developed RAG2/IL2RG deficient pigs using CRISPR/Cas9 as a large animal model with the novel application of cancer xenograft studies of human pancreatic adenocarcinoma. In this proof-of-concept study, these pigs were successfully generated using on-demand genetic modifications in embryos, circumventing the need for breeding and husbandry. Human Panc01 cells injected subcutaneously into the ears of RAG2/IL2RG deficient pigs demonstrated 100% engraftment with growth rates similar to those typically observed in mouse models. Histopathology revealed no immune cell infiltration and tumor morphology was highly consistent with the mouse models. The electrical properties and response to irreversible electroporation of the tumor tissue were found to be similar to excised human pancreatic cancer tumors. The ample tumor tissue produced enabled improved accuracy and modeling of the electrical properties of tumor tissue. Together, this suggests that this model will be useful and capable of bridging the gap of translating therapies from the bench to clinical application.

Highlights

New therapies to treat pancreatic cancer are direly needed
While healthy porcine tissues and mouse models have been critical for therapeutic development, we have found the lack of appropriate pancreatic cancer tissues to be a limitation
In an effort to circumvent the limitations related to animal models of pancreatic cancer and further advance the optimization of irreversible electroporation (IRE) utilizing human pancreatic cancer tissue, we developed an immunodeficient porcine model that has proven ideal for human cell transplantation and xenograft s tudies[31,32,33,34,35]

Summary

Introduction

New therapies to treat pancreatic cancer are direly needed. efficacious interventions lack a strong preclinical model that can recapitulate patients’ anatomy and physiology. The availability of abundant, high quality tumor tissue is a major limitation in the development of medical devices that require ex vivo modeling and validation This is especially true in pancreatic cancer research, where human specimens from patients are typically highly limited and restricted to small biopsies. While mice are excellent bioincubators for human tissue and cell lines, the size of tumor tissue is often limited due to the relatively small size of the animal We have found this to be a significant limitation in the development of irreversible electroporation (IRE) based therapeutic strategies. IRE has been successfully adapted for the treatment of tumors considered, until now, inoperable due to their proximity to critical structures such as blood vessels, nerves, and d ucts[27,28,29,30]

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