Researchers from Vanderbilt University Medical Center have demonstrated in a precision-based clinical trial that a magnesium supplement increases gut bacteria in humans that have been shown to synthesize vitamin D and inhibit colorectal cancer carcinogenesis.

However, the effect was observed primarily in females — an outcome that the researchers surmised may be attributable to the role that estrogen plays in shifting magnesium from circulation into cellular uptake.

Intestinal microbiome data and colonoscopy results were analyzed from participants who were randomized by whether they had the TRPM7 genotype, which plays a crucial role in regulating magnesium and calcium uptake.

Previously, the investigators showed in the same randomized trial that magnesium enhances the synthesis of vitamin D and increases the blood levels of vitamin D. The findings from the current study suggest that magnesium also increases the gut synthesis of vitamin D, which does not go to the blood and takes effect locally.

These results from the Personalized Prevention of Colorectal Cancer Trial were published Sept. 12 inThe American Journal of Clinical Nutrition. 

“Our previous study showed magnesium supplementation increased blood levels of vitamin D when vitamin D levels were low,” said Qi Dai, MD, PhD, professor of Medicine. “The current study reveals that magnesium supplementation also increases the gut microbes which have been shown to synthesize vitamin D in the gut without sunlight and locally inhibit colorectal cancer development.”

The participants were divided into two arms, one that received the magnesium supplement and another that received a placebo. Their gut microbiome was analyzed from stools, rectal swabs and rectal tissues. Among participants with adequate TRPM7 function, the magnesium supplement increased Carnobacterium maltaromaticumand Faecalibacterium prausnitzii, which were previously found to work synergistically to increase vitamin D and decrease colorectal carcinogenesis. Among those with inadequate TRPM7function, the magnesium supplement reduced the abundance of F. prausnitziiin rectal mucosa.

Among 236 participants who all had a history of colorectal polyps, 124 underwent colonoscopies after completing the trial with a 3.5-year median follow-up time. A higher abundance of F. prausnitzii in rectal mucosa was associated with an almost threefold increase in developing additional polyps.

The findings suggest that magnesium supplementation treatment may decrease colorectal cancer risk in individuals with inadequate TRPM7function. All together, these findings provide new insights into the interplays between nutrition and gut microbiome contributing to colorectal carcinogenesis and establish the foundation for a precision-based strategy for prevention of colorectal cancer in high-risk populations.

The researchers received support from the National Cancer Institute (R01 DK110166, R01 CA149633 and R03 CA 189455) and the Vanderbilt-Ingram Cancer Center Endowment Fund. Dai and Martha Shrubsole, PhD, Ingram Professor of Cancer Research and research professor of Medicine, are principal investigators of the grant that funded the microbiome research from the National Institute of Diabetes and Digestive and Kidney Diseases (DK110116).

Other major Vanderbilt authors on the study include Elizabeth Sun, Xiangzhu Zhu, MD, MPH, Reid Ness, MD, MPH, Harvey Murff, MD, MPH, and Lei Fan, MD, PhD. The first author, Elizabeth Sun, a medical student at Vanderbilt University School of Medicine, was elected for an Early Investigator Travel Award, a young investigator lightning talk, and an in-person poster presentation at the Precision Nutrition Forum and PREDIMED Omics Symposium 2025 held by Harvard University.

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A colorectal cancer research team led by Robert Coffey, MD, has received a prestigious Specialized Programs of Research Excellence (SPORE) grant renewal totaling $12.6 million from the National Cancer Institute (NCI) for a five-year period.

The grant marks ongoing funding of the GI SPORE awarded to Coffey’s team, which dates back to its inception at the Vanderbilt-Ingram Cancer Center in 2002. Currently, Vanderbilt-Ingram is one of only four cancer centers in the United States with GI Cancer SPORE funding. The team has made numerous discoveries over the past 23 years, and it plans to build upon those achievements with the goal of “drugging the undruggable.”

Applications for SPORE funding are intensely competitive. SPORE grants are highly sought after because they show that a cancer center demonstrates scientific excellence, promotes collaboration, maintains robust research programs and merits substantial funding — factors that are key determinants for an NCI designation as a Comprehensive Cancer Center.

“Our success is built upon clinical and basic investigators working closely together with patient advocates,” said Coffey, Ingram Professor of Cancer Research, professor of Medicine and of Cell and Developmental Biology, and co-director of the Epithelial Biology Center.

Coffey, the grant’s principal investigator, is joined by clinical co-leaders, basic science co-leaders, and patient advocates in pursuing three projects that are aimed at targeting three mechanisms of colorectal cancer progression: immune exclusion, MYC activation, and Wnt pathway activation. Each project has an embedded patient advocate to ensure that each project is focused on its translational goal.

“Securing SPORE funding is an achievement to be recognized, but having a program funded for 23 years is truly outstanding,” said Ben Ho Park, MD, PhD, the Benjamin F. Byrd Jr. Professor of Oncology and director of Vanderbilt-Ingram. “Congratulations go to Dr. Coffey, the principal investigator, and to the entire research team for a job well done. With this grant renewal, they are building upon years of rigorous and innovative research and are making great progress towards developing new therapies for gastrointestinal cancers that are recalcitrant to current treatment modalities.”

The team dedicated to the project of overcoming immune exclusion in microsatellite stable colorectal cancer includes clinical co-leader, Jordan Berlin, MD, associate director for Clinical Research at Vanderbilt-Ingram, Cornelius Abernathy Craig Professor of Medicine and director of the Division of Hematology and Oncology, along with basic science co-leaders Coffey and Ken Lau, PhD, professor of Cell and Developmental Biology and of Surgery and director of the Center for Computational Systems Biology.

Immunotherapies such as immune checkpoint blockade inhibitors have proven effective for a number of cancers, including a subset of colorectal cancer, but not for the 85% to 90% of colorectal cancers that are deemed microsatellite stable. The team will launch a clinical trial to see if an investigational drug can spur response in microsatellite stable colorectal cancers when combined with the immunotherapy drug pembrolizumab.

The investigators will also determine whether response can be tracked by monitoring proteins associated with plasma supermeres, novel nanoparticles discovered by the Coffey lab.

The team dedicated to targeting MYC is led by clinical co-leader, Kristin Ciombor, MD, MSCI, co-leader of the Gastrointestinal Cancer Research Program at Vanderbilt-Ingram, Ingram Associate Professor of Cancer Research and associate professor of Medicine. The basic science co-leader is William Tansey, PhD, associate director for Shared Resources and co-leader of the Genome Maintenance Research Program at Vanderbilt-Ingram, Ingram Professor of Cancer Research and professor of Cell and Developmental Biology.

Overexpression of the MYC gene is common in colorectal cancer, and the team will delve into whether a site on the protein WDR5 that plays a role inMYC action can be targeted for therapeutic benefit for patients with unresectable colorectal cancer. The investigators will lead a clinical trial to investigate the tolerability and antitumor efficacy of an experimental therapy developed by Stephen Fesik and Tansey in the last cycle of the SPORE award.

The team developing an inhibitor drug for the Wnt pathway is led by clinical co-leader, Cathy Eng, MD, co-leader of the Gastrointestinal Cancer Research Program at Vanderbilt-Ingram, David H. Johnson Professor of Surgical and Medical Oncology and professor of Medicine, along with basic science co-leaders Stephen Fesik, PhD, the Orrin H. Ingram II Professor of Cancer Research and professor of Biochemistry, Pharmacology and Chemistry, and Ethan Lee, MD, PhD, professor of Cell and Developmental Biology and of Pharmacology.

Activation of the Wntpathway is a characteristic of colorectal cancer and has been notoriously hard to target without adverse toxicities. The Wnt-focused team will be developing a first-in-class inhibitor that could revolutionize the landscape of treatment for colorectal cancer due to its dependence on Wnt activation for establishment and progression.

The GI SPORE grant also cultivates future scientific advancement through the Career Enhancement Program at Vanderbilt-Ingram, which recruits young investigators and helps them develop into independent researchers. Participants can apply for seed funding — small grants that help them establish the basis for research achievements that merit additional funding.

These programs are led by Karen Winkfield, MD, PhD, associate director for Community Outreach and Engagement at Vanderbilt-Ingram, Ingram Professor of Cancer Research and professor of Radiation Oncology, and Richard Peek, MD, the Mina Cobb Wallace Professor of Immunology and professor of Medicine and Pathology, Microbiology and Immunology.

Overall, this grant is a large accomplishment that shows the importance of team science and collaboration of basic and clinical leaders together with patient advocates to propel advances in the diagnosis and treatment of GI malignancies.

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Aimal Khan, MD, assistant professor of Surgery at Vanderbilt University Medical Center, noticed the puzzled or anxious expressions of patients trying to fully comprehend what he was saying during preoperative consultations, so he devised visual aids — three-dimensional models of the lower digestive tract. 

The 3D models allowed patients to easily distinguish the ascending colon from the sigmoid colon, along with other parts of the digestive system. Patients could actually see where the surgery would occur, and Khan noticed that they asked more questions, felt more confident and seemed less anxious.  He devised a study to determine whether his personal observations were scientifically valid. 

The study, which was published June 3 in JAMA Network Open, determined that the 3D models made patients feel they played a bigger role in decision-making and that their anxiety levels decreased. 

The patients were scheduled for partial or complete colon and/or rectal resections for colorectal cancer, diverticulitis or inflammatory disease. Fifty-one patients participated in the study with 28 receiving consultations using the 3D models and 23 receiving conventional consultations. The patients in the 3D arm of the study reported a significantly higher involvement in shared decision-making and significantly reduced anxiety levels compared to the other patients. 

Khan and five other Vanderbilt surgeons conducted the study from March 2022 to June 2023.  

“Using 3D models during consultations allowed our patients to truly visualize their surgery, which not only empowered them to take an active role in decision-making but also significantly eased their anxiety. This approach has the potential to transform how we communicate complex information to our patients. We are currently working with surgeons from other specialties, including thoracic surgery, ENT and surgical oncology, to validate these findings in a multicenter randomized trial,” Khan said. 

The findings are important because other studies have shown that improvements in shared decision-making are associated with reduced hospital stays, lower health care utilization, improvement in patient-reported health outcomes and fewer emergency department visits.  

The 3D models used in the study were developed in collaboration with the Department of Radiology. The modular designs, which were made with 3D printing, allowed each segment of the colon and rectum to be magnetically detached and reattached. 

To the knowledge of the study’s authors, this is the first randomized clinical trial to compare the effectiveness of a 3D-printed model with usual care on colorectal surgery patients’ involvement in decision-making, anxiety and education. 

Other Vanderbilt researchers who authored the study are Danish Ali, MD, Shannon McChesney, MD, Michael Hopkins, MD, Molly Ford, MD, Roberta Muldoon, MD, Timothy Geiger, MD, MMHC, Alexander Hawkins, MD, MPH, Georgina Sellyn, MA, Hillary Samaras, RN, and Dann Martin, MD, MS.

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Andreana Holowatyj, PhD, MSCI, assistant professor of Medicine, has been named to the 40 Under 40 In Cancer Class of 2025 by the Association for Value-Based Cancer Care.

This year’s class was selected from more than 3,000 nominations. The awards initiative identifies and recognizes contributions across the field of cancer by rising stars and emerging leaders under the age of 40. 

Holowatyj’s research is focused on early-onset cancers, including colorectal and appendiceal cancers. She has received the National Cancer Institute’s Method to Extend Research in Time (MERIT) Award to support her ongoing investigation into how early-onset colorectal cancer and its treatments impact reproductive health. MERIT Awards provide longer-term funding than is typical for most grants to early-stage investigators whose research competence and productivity are distinctly superior and who are highly likely to continue to perform in an outstanding manner. As part of this Award, Holowatyj established and leads the Preserving Fertility After Colorectal Cancer (PREFACE) clinical study, which is currently recruiting patients.  

She is focused on providing evidence-based guidance that will ultimately improve clinical care and outcomes for individuals ages 18 to 49 when diagnosed with cancer. Holowatyj and her team discovered that 1 in 2 young cancer patients report that a health care provider involved in their cancer care did not discuss options to preserve fertility prior to starting cancer treatment. 

Her research has been published in high-impact medical research journals and has led to clinical practice changes and revisions to consensus guidelines. She has also been invited to serve on several international committees, including the American Joint Committee on Cancer Lower Gastrointestinal Tract Expert Panel that updates clinical cancer staging systems, the Fight Colorectal Cancer Global Early-Onset Colorectal Cancer Think Tank, and as the inaugural chair of the Scientific Advisory Board for the Appendix Cancer Pseudomyxoma Peritonei (ACPMP) Research Foundation. This year, with the support of the ACPMP Research Foundation, she led an expert recommendation report in the journal Nature Reviews Cancer that identified six key research priority areas to deliver a fundamental understanding of appendiceal tumors and to improve treatments and outcomes for patients with this rare cancer.

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Colorectal cancer is the second most common cause of cancer-related deaths worldwide, according to the World Health Organization. Understanding factors that contribute to the development of colorectal cancer could point to new targets for treating the disease at earlier stages, when survival rates are highest. 

Nicholas Markham, MD, PhD, assistant professor of Medicine, and colleagues are exploring how bacteria in the colon may contribute to cancer development. They previously showed that C. diff (Clostridioides difficile) isolated from human colorectal cancer samples accelerated tumorigenesis in the colon in a mouse model of intestinal cancer. 

Now, they have combined single-cell RNA sequencing, spatial transcriptomics and immunofluorescence to build a multiomic atlas of gene expression and protein abundance in C. diff-associated colorectal tumorigenesis. 

They report in The Journal of Pathology that the protein DMBT1 (Deleted in Malignant Brain Tumors 1) shows striking differences in regulation in areas of the colon with inflammation versus dysplasia (abnormal cellular changes). DMBT1 is a protein with roles in mucosal immune defense and epithelial cell differentiation. 

In a mouse model, the researchers found that expression of DMBT1 increases in normal absorptive colon cells exposed to C. diff, but that its expression is reduced in dysplastic areas compared to normal adjacent tissues. 

Immunofluorescence studies confirmed that DMBT1 protein was downregulated in dysplastic regions from three mouse models of colonic tumorigenesis and in colorectal precancerous adenomas from human samples. Using mouse and human organoids, the researchers implicated WNT signaling in the downregulation of DMBT1 mRNA and protein. 

The findings suggest that loss of DMBT1 could be a mechanistic link between bacterial infection and colorectal cancer development. Further studies will explore how DMBT1 might function to limit tumorigenesis. 

Emily Green, a graduate student in the Molecular Pathology and Immunology program, is the first author of the study. Collaborators at Johns Hopkins University School of Medicine contributed to the study. The research was supported by grants from the Department of Veterans Affairs (BX005699, BX002943) and the National Institutes of Health (P30DK058404, P30CA068485, R00CA230192, P50CA236733).

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