Tufts Medical Center’s Jutin Roper, MD and colleagues at MIT’s Koch Institute for Integrative Cancer Research have developed new techniques that can precisely create tumors in mice that resemble human colon cancer. These advances should help scientists learn how cancers form and test new treatments. The research is published online yesterday in the journal Nature Biotechnology.
For many years, researchers have used two distinct approaches to study human cancer. The first approach is to grow cancers in a two-dimensional dish, called a cancer cell line, which can also be grown in mice. However, all of the cells in a cancer cell line are similar, and therefore do not reflect the complexity of a human cancer. The second approach is to engineer mice with one or more genetic mutations, which can take years if more than one mutation is involved.
“The process of developing and testing therapies for cancer is slow, expensive, and inefficient because of the limitations of the tools we have,” said Dr. Roper, Director of the Center for Hereditary Gastrointestinal Cancer and Assistant Professor of Medicine in the Division of Gastroenterology and Molecular Oncology Research Institute (MORI) at Tufts Medical Center. “We need more accurate and faster ways to model human cancer.”
The team took colon tissues from mice and grew them in a dish as three-dimensional “mini-intestines” called organoids. They used a gene editing system known as CRISPR to introduce mutations in a gene called APC, which is mutated in 80 percent of colon cancer patients, and another important cancer gene called P53. Then, through colonoscopy, they inserted these mutated organoids into mouse colons to create tumors that closely resemble human cancer. Dr. Roper and his colleagues also used CRISPR technology to directly modify genes in the colon to form tumors.
The team also took tumor tissue from colon cancer patients, formed three-dimensional organoids in the lab, and then transplanted the cancer samples into mice. This resulted in colon tumors that reproduced the unique characteristics of an individual’s malignancy. This novel technique opens the door to personalized treatments – an individual’s own cancer can be quickly grown in a mouse model in order to test the efficacy of different cancer treatments.
“What’s exciting is that CRISPR gene editing, organoid cultures, and transplantation technologies can be used for studying just about any kind of cancer, as well as other diseases,” said Dr. Roper. Tyler Jacks, PhD, Executive Director of the Koch Institute, has used CRISPR to generate lung and liver tumors in mice.
The new techniques are also exciting for another reason – they may give scientists clues about how to stop the cancer from spreading to other parts of the body, the major cause of death from colon cancer. In Dr. Roper’s models, mouse and human cancer tissues form colon tumors that spread to the liver, which closely mimics how human colon cancer progresses.
Philip Tsichlis, MD, Executive Director of the Molecular Oncology Research Institute, James Yoo, MD, Chief of Colon and Rectal Surgery, and Lillian Chen, MD from the Division of Colon and Rectal Surgery are Tufts Medical Center collaborators on this latest study. Ömer H. Yilmaz, MD, PhD, Assistant Professor of Biology at MIT’s Koch Institute, is the senior author.
In his clinical practice, Dr. Roper diagnoses patients with inherited conditions that cause early and aggressive cancers, and performs colon examinations (i.e., colonoscopy) to remove polyps that can grow into colon cancers. However, he says, “Despite our best efforts so far, 50,000 Americans are expected to die this year from the disease, which is very disappointing. My hope is that the new platforms for cancer research that we report in this paper will enable scientists to discover new ways to prevent and treat colon cancer.”
Dr. Roper’s research was funded by the National Cancer Institute / National Institutes of Health, the V Foundation, the Department of Defense, and the Tufts Clinical and Translational Science Institute (CTSI).
Posted March 2018
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