Cancer modeling thinks big with the pig

Large animal models can be important translational steps between basic research in rodents and clinical care in humans. Ever thought about a pig? The patient had four legs and a tail. But it wasn’t a rat. Surgeon Mark Carlson had some preclinical experience with rodent models, but he had never worked on the animal his colleagues at the University of Nebraska Medical Center (UNMC) were proposing: pigs, part of a study about hemorrhage and hemostasis. “But you know, it’s surgery,” he recalls thinking. How difficult could it be? Trotting on: Biomedical researchers are picking up the pig and creating porcine models of a variety of cancers. Credit: (design) E. Dewalt/SpringerNature; (Hoofprints) MeggSt/Getty; (Petri Dish) luchschen/Getty The surgical techniques Carlson used in humans patients were easily adapted to the pig, and he found himself enthusiastic about a larger animal model. “I began to really look around to see what else I could do with pig models,” Carlson says. He came to cancer, pancreatic in particular, an area he knew was going to difficult but “but also with a very high potential yield,” he says. UNMC already had an established research program for pancreatic cancer, a disease with a stubbornly poor prognosis if not caught early. “We’ve kind of hit a wall in terms of improving patient survival,” Carlson says, so he started asking other scientists around campus what they thought about introducing the pig as a new preclinical model. “About half of them were very enthusiastic,” he says. And the other half? To them, a pig model seemed a bit absurd. “But the idea was strong enough,” he says. Nor was he the only one thinking about porcine models of cancer. “I realized that the field was not empty. Sparsely populated, but not empty.” Scientists and clinicians have valued the pig for its anatomical and physiological similarity to humans for decades. Surgeons often train on the pig before turning to a patient, and the pig is a large animal option for device and pharmaceutical companies to test their new developments before heading to the clinic. Pigs might soon help abate organ shortages too, if the kinks to xenotransplantation can be fully worked out. But cancer is a relatively more recent frontier. A handful of spontaneous and chemically induced porcine models have been around since the early 2000s, but tumors in those models can be hard to predict and labor-intensive to produce1. And the natural occurrence of cancers in pigs is somewhat of a mystery. “They’re a food item in western countries, and so they’re not allowed to live to a ripe old age like dogs or cats are,” Carlson says, “We really don’t know what kind of cancer pigs get naturally.” Another complication: cancer is often a disease of age, whereas the pigs available are juveniles. “If you want to make them into old pigs, you have to sit around for a few decades and wait for them to get old,” he says. But advances in the genetic engineering of swine are opening new doors to cancer research, without the wait. When the genome of the domestic pig, Sus scrofa, was sequenced in 2012, researchers saw that the animals have genetic as well as anatomical and physiological similarities to humans that they could take advantage of too. Investigators like Lawrence Schook, a professor of animal sciences and radiology at the University of Illinois who was involved in the sequencing effort, started exploring whether a new model was possible. “We asked a very, very fundamental question,” says Schook: if the pig really was so similar to humans, would the same driver mutations found in cancer patients also cause cancer in pigs? Mutations to genes like P53 and KRAS, two of the most commonly mutated oncogenes founds in human cancers. The answer that he, and others that are picking up the pig, are discovering, is ‘Yes.” A pig walks into the clinic… Like many biomedical researchers, Schook started small, studying genetic resistance to diseases like cancer in the little workhouse that is the lab mouse. Genetic approaches were advancing in the mouse and you could do a lot with them, he says, but the mouse can only take you so far. “The mouse is a great animal to do all the logistics on mutation and things like that,” he says. “But when you get into the therapeutic side, the translation side, that’s where the weakness comes. Because you can’t use instruments, you can’t use radiation. When you talk about mice, it just is different. A different animal.” His career took a decidedly larger turn towards an animal more often found down on the farm: the pig. “I’ve always viewed pigs as a big mouse,” says Schook. The size of the pig is a big advantage (Box 1). While domestic agricultural animals can top out near 800 pounds, the “miniature” strains developed in recent years for biomedical research can be kept, with the right diet, at a more manageable 150–200 pounds. That puts them into a similar weight class to the organism that animal models are intended to model: the human. The mouse, by comparison, is tiny: an adult will weigh in around just 20 to 30 grams. A small animal means small anatomy. Adrienne Watson is a scientist at Recombinetics who has been involved in the development of a porcine model of Neurofibromatosis Type I (NF1), a rare pediatric disease that causes nervous tissue tumors. Many NF1 patients will develop optic pathway gliomas—tumors on the nerves of the eye. Mouse models of NF1 will develop these, but their optic nerve presents a challenge: it’s about the size of a piece of dental floss. “To image it on an MRI machine, to go in and perform surgery, which is what they do with patients with problematic optic pathway gliomas, is nearly impossible,” says Watson. The pig is the right scale. Pig in an MRI: Working with a human-sized animal means researchers can use human-sized equipment, like MRI machines to recreate how cancer in human patients is assessed and treated. Credit: L. Schook “The pig is large enough to do things like imaging, so you can put a pig into a human MRI machine, a human CT machine, a human PET scanner. You can do radiation therapy; you can do surgery, all these things that are really key in patient care,” Watson says. That means care, and treatment, can more closely replicate what occurs in the clinic. As they developed their NF1 model, Watson’s collaborator Christopher Moertel, a clinician at the University of Minnesota, would give the full assessment intended for humans to the pigs. “They were pretty much treated just like if a patient with NF1 walked into a clinic,” says Watson, with similar biopsy, MRI, and CT protocols. As a cancer model, a pig’s absolute size has a relative advantage too, says Dhanansayan Shanmuganayagam, a scientist at the University of Wisconsin-Madison who has worked with pigs for the past twenty years, initially for cardiac research. In rodent models of cancer, tumors often outgrow the relative size observed in a human (...truncated)