by Sarah Glass

Vanderbilt University Medical Center has received a five-year, $5 million grant from the National Cancer Institute to study precancerous lesions and early cancers in the colon, with the goal of developing new ways to prevent colorectal cancer, the nation’s second leading cancer killer.

Robert Coffey, MD, Martha Shrubsole, PhD, and Ken Lau, PhD, are VUMC’s project leaders for the grant, one of five awarded this year under the institute’s Translational and Basic Science Research in Early Lesions (TBEL) program.

The TBEL program focuses on understanding cellular changes that allow tumor development, including microenvironmental interactions mediated by immune cells and microbes that can contribute to slowing down or speeding up tumor growth.

Coffey, the Ingram Professor of Cancer Research and director of the Epithelial Biology Center at VUMC, sees the TBEL program as a direct extension of the team’s Colon Molecular Atlas Project, part of the national Human Tumor Atlas Network (HTAN).

“Our accomplishments as one of 10 sites funded for the HTAN initiative has contributed to us being in elite company as one of the sites selected for the TBEL, to look at mechanisms behind those interactions identified through the HTAN initiative,” he said.

Coffey is internationally known for his work on the trafficking of extracellular proteins, or ligands, that bind the epidermal growth factor receptor (EGFR), and the role they play in gastrointestinal cancer.

His track record of high-impact research continues with the grant’s focus on precancers of the colon.

Lau, associate professor of Cell and Developmental Biology, said the close collaborative relationship between Vanderbilt University and VUMC will “facilitate success in this patient-centric project by bringing together expertise in both basic and clinical sciences.”

Lau’s work in single-cell technologies has led to important discoveries regarding epithelial tissue and the microenvironment’s impact on it.

Shrubsole, research professor in the Division of Epidemiology, has collaborated closely with Coffey and Lau in the HTAN initiative, and will continue this fruitful partnership in the TBEL grant with the inclusion of Cindy Sears, MD, professor of medicine at John Hopkins University.

Shrubsole has been a leader in studies of cancer health disparities and has played crucial roles in epidemiological studies and clinical trials.

The TBEL grant will undertake three projects:

Project 1, led by Coffey, will determine the role that a protein called DPEP1 plays in immune cell recruitment and phenotype modulation in adenomas, or benign tumors.

Using a unique mouse model called the Catchup mouse that has bright red-fluorescent neutrophils, a type of immune cell, the researchers will try to determine at which stage in colon cancer development neutrophils play a pro-tumorigenic role.

Project 2, led by Shrubsole and Sears, is focused on how the microbiome, the complex ecosystem of microorganisms in the gut, and specifically E. coli bacteria, which produce the toxin colibactin, affects the probability of colonic pre-cancers progressing.

They will use a combination of epidemiologic studies and human precancerous colonoids, tissue cultures derived from stem cells in the colon. An aim of the research is to help identify individuals at a higher risk for progressive precancers who may benefit from new prevention or surveillance strategies.

Project 3, led by Lau, will use spatial genomics technology to decipher tumor co-evolution with the immune microenvironment.

A goal is to identify mechanisms of tumor progression, such as immunosuppression, that may predict the probability of colorectal polyps progressing to cancer.

Identification of key transition periods and genetic alterations may lead to new targets to prevent or treat colorectal cancer.

Each project has overlapping and cross-cutting elements that will inform the others.

Overall, the TBEL grant will allow researchers to study what factors contribute to the advancement of precancerous lesions to colorectal cancer.

This, in turn, may lead to the identification of new biomarkers, risk factors and prediction tools that clinicians can consider when treating patients.

“This new TBEL grant, by building on the success of our HTAN study, integrating basic and translational approaches, and evaluating three different avenues of colorectal cancer progression, will be instrumental in advancing our understanding of colorectal carcinogenesis,” Shrubsole said.

VUMC’s TBEL grant is U54CA274367.