by Tom Wilemon
A trans-institutional team of researchers at Vanderbilt University Medical Center and Vanderbilt University has received an $11 million Cancer Moonshot grant to build a single-cell resolution atlas to map out the routes that benign colonic polyps take to progress to colorectal cancer, the third most common cancer among both men and women in the United States.
The work entails gathering thousands of data points per cell for each participant and then transforming that information into multidimensional geographic maps that enable scientists to study interactions among tumor cells, the microbiome and the immune microenvironment.
Vanderbilt is one of only five institutions designated a Pre-Cancer Atlas (PCA) Research Center by the National Cancer Institute (NCI). The four other institutions will lead similar efforts involving precancerous lesions of the skin, lung and breast.
The principal investigators leading the Colon Molecular Atlas Project (Colon MAP) are Robert Coffey, MD, Ingram Professor of Cancer Research and director of the Epithelial Biology Center at VUMC; Ken Lau, PhD, assistant professor of Cell and Developmental Biology, and Martha Shrubsole, PhD, research professor of Medicine, Division of Epidemiology. They will lead an effort to identify which people are at greatest risk for colon cancer, discover cell characteristics that could lead to chemoprevention strategies and possibly recommend changes in screening and surveillance practices.
“We are indeed fortunate to receive this award; it places us among a small group of elite institutions, including Stanford, Harvard and Duke,” Coffey said.
Congress passed the 21st Century Cures Act in December 2016 authorizing $1.8 billion to fund the National Cancer Moonshot — a federal recommitment to curing cancer diseases and accelerating the pace of advancements. Former Vice President Joe Biden called for the initiative in October 2015 when he announced that he would not run for president but would instead focus on advancing cancer research.
A 28-member blue ribbon panel set priorities for Cancer Moonshot, and the Colon MAP initiative follows through on several of them, including early cancer detection and enhanced data sharing. The members of the blue ribbon panel included Jennifer Pietenpol, PhD, Executive Vice President for Research at VUMC, director of the Vanderbilt-Ingram Cancer Center and B.F. Byrd Jr. Professor of Oncology.
Key institutional strengths helped VUMC receive the PCA Research Center Designation: single-cell technologies developed at the Epithelial Biology Center and an epidemiologic study established in 2002 when Vanderbilt was first awarded an NCI GI Specialized Programs of Research Excellence (SPORE) that focuses on colorectal cancer and is led by Coffey.
Lau is an expert in data science approaches to sing-cell analysis, including single-cell RNA-sequencing and multiplex immunofluorescence (MxIF).
“This is really an application of ‘Big Data’ science to a problem in cancer biology — to model how the spatial ecosystem of the tumor changes during the progression from a benign polyp to a malignant cancer,” Lau said. “We use a microfluidic approach to encapsulate individual cells in oil-liquid emulsions, essentially treating each droplet as a test tube for performing transcriptome-wide analysis on thousands and thousands of cells. We really look forward to building upon the foundations of the Center for Quantitative Sciences headed by Dr. Yu Shyr and the new Data Science Institute to apply computational learning techniques to this complex problem.”
New technology developed at Vanderbilt allows researchers to examine lab samples more efficiently.
“MxIF allows up to 40 proteins to be examined on a single tissue section,” Coffey said. “It was developed through a National Institutes of Health common fund partnership grant with GE Healthcare and my lab. The method and supporting analytical tools are being continuously refined through efforts within the Epithelial Biology Center.”
A key research partner on the Colon MAP initiative is Cindy Sears, MD, of Johns Hopkins Bloomberg School of Public Health, whose focus is the biofilm that resides over different colon cancer subtypes and possibly a large portion of adenomas as well, Coffey said.
“Within this mucus layer, there are different microbes, different populations that have been shown to even invade into the epithelium, eliciting a response by immune cells within the stroma,” Coffey said. “She has some very provocative data that it may contribute to colorectal cancer progression. We are taking a holistic single-cell approach to studying adenomas — not only the adenoma itself, but also its surrounding microenvironment.”
Shrubsole said the team will build on the SPORE infrastructure. Some patients undergoing colonoscopies or surgeries at VUMC will be asked to take part in Colon MAP. Patients recruited for the study will be between the ages of 40 and 75.
“We’re looking to recruit 1,800 people for Colon MAP,” Shrubsole said. “We will be collecting the precancerous lesions, but we also need samples from people without them to be able to compare the colon tissue between people who do and do not have polyps. Our comprehensive molecular epidemiologic design will allow us to answer many research questions about risk factors for progression and potential targets for new cancer screening and prevention strategies.”
Others at VUMC involved with Colon MAP are Yu Shyr, PhD, Harold L. Moses Chair in Cancer Research; Qi Liu, PhD; Kay Washington, PhD, MD; Timothy Geiger, MD; Reid Ness, MD; Gregor Neuert, PhD, and Meghan O’Loughlin, program manager of the Epithelial Biology Center.
“This is by its nature a very collaborative and community effort to complete this Moonshot award,” Shrubsole said. “None of our individual groups can do this alone.”
The $11 million grant period is from September 2018 to June 2023. The data will be shared with all cancer researchers as part of the Human Tumor Atlas Network (HTAN).
In addition to the five PCA Research Centers, five other Human Tumor Atlas centers will be focused on creating multidimensional tumor atlases for colon cancer, lung cancer, pancreatic cancer, breast cancer, skin cancer and pediatric cancers.
Stanford is a PCA Research Center for familial adenomatous polyposis, a genetic syndrome that causes colon cancer so it will complement Vanderbilt’s efforts to study sporadic adenomas. Three of the 10 HTAN awards will be focused on colorectal adenomas or colorectal cancers.
