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Breaking it Down: How the Chemistry of Digestion is Uncovering Sex-Specific Causes of Colon Cancer

December 09, 2018

Sometimes the tiniest clues can solve the biggest mysteries.

A new technology called metabolomics allows researchers to explore the small chemicals formed and used during digestion as a window into the formation of diseases such as colon cancer, seeking early warning signs and potent tactics for prevention.

“Women have a lower rate of colon cancer than men but a higher prevalence of right-sided colon cancer, which is associated with a 20 percent increased risk of death compared with cancer of the left side,” said Dr. Caroline Johnson, a leading expert in metabolomics research. “And we don’t know why.”

With a Women’s Health Research at Yale Pilot Project grant, Dr. Johnson is answering the question: Can digestive chemistry uncover sex-specific causes of colon cancer? The answer promises crucial clues about the biological underpinnings of this disease leading toward effective therapies for women who develop this more lethal type.

A Type of Colon Cancer More Deadly in Women

Colon cancer is the second most common cancer diagnosed among women worldwide. In the United States, colon and rectal cancer are together the number three cause of cancer death for women and the number two cause for men. This year, more than 50,000 people are expected to die of the disease.

With WHRY’s grant, Johnson is investigating “downstream” products of what we consume, what our hormones produce, and what bacteria reside in the colon. With this information, she is learning what may lie behind this sex difference in colon cancer risk and what can be done to prevent the worse outcomes for women.

“This is the first study of its kind,” said Dr. Carolyn M. Mazure, Director of WHRY. “It is unique because of the innovation and the power of metabolomics and because of Dr. Johnson’s expert training in this new biologic technique. We are so pleased to have her at Yale, where she was recruited specifically to develop this new technology and examine the causes of colon cancer.”

Trained at Imperial College London as an analytical chemist and then at The Scripps Research Institute and The National Institutes of Health, Johnson has, through her WHRY-funded study, already begun to uncover markers of colon cancer in women and men that can aid in early diagnosis and treatment and guide strategies for prevention.

“Our early results are revealing multiple pathways that show a significant difference — not due to chance — between how colon cancer develops in women and men,” Johnson said, noting how the work will benefit all women but particularly black women, who are at higher risk for colon cancer compared with other races or ethnic groups. “And we have many promising leads to follow up.”

A Unique Study Producing Significant Results

As part of this study, Dr. Johnson and her colleague Dr. Sajid Khan from Yale School of Medicine have acquired a colorectal tumor tissue biobank with help from colleagues at Memorial Sloan Kettering Cancer Center (MSKCC) in New York. They have obtained 3,000 tissue samples from MSKCC’s unique biobank of colorectal tumors, which were individually collected during surgery and immediately flash frozen into liquid nitrogen — one of the very few large biobanks available for metabolomics analysis.

After studying the samples, Dr. Johnson identified 207 that met the study’s criteria. For example, her team excluded samples from patients who underwent chemotherapy before surgery, which can affect metabolite levels in colon tissue.

Her laboratory has successfully optimized the experimental procedure, extracting each sample to purify the metabolome, performing liquid chromatography to separate the thousands of metabolites within each sample, and conducting mass spectrometry to measure masses within a sample using a new, sensitive machine that requires only a small amount of each sample to determine the weight and abundance of each metabolite.

Johnson continues to analyze the data and run tests. But initial results show great promise.

The tests have demonstrated that when comparing tumor tissues from women with stage 3 right-sided colon cancer (RCC) to tissues from men with stage 3 RCC, there is a difference in the production of saturated and polyunsaturated fatty acids (PUFAs).

This is quite informative because fatty acids are important small molecules that can come from the diet or can be made from the cells themselves when supply is low. They play crucial roles in maintaining cellular structures and function, and changes in dietary intake or PUFA metabolism contribute to cancer risk and progression.

In addition, Johnson has found that Vitamin E metabolism is decreased in women with RCC. This is important information because Vitamin E serves to protect fatty acids from oxidative damage that can cause cancer growth.

Much More to Learn

Dr. Johnson and her team are just getting started.

The study will next examine how the stage of cancer effects fatty acid levels and whether fatty acid metabolism genes are altered in women with RCC, thus confirming whether cellular replication is different between men and women with RCC. The study will also carry out experiments to determine how fatty acids are regulated by sex hormones and determine if these metabolites can be used as biomarkers for the aggressiveness of RCC.

Dr. Johnson has leveraged her early findings to earn an external two-year grant to advance this work, allowing for additional mass spectrometry analysis to correlate metabolites with patient outcomes. And she is gathering additional clinical data on the sample subjects in search of any significant connections that might offer clues about the sources of their particular metabolites.

“The more we learn about a patient’s race, diet, hormone levels, pregnancy history, and cancer treatment, the more we can determine how all of these factors and their metabolome interact during the progression of cancer,” Johnson said. “And then we can better predict — and possibly prevent — the worst types of cancer.”

She has also successfully shared her work with influential colleagues, including a planned presentation at the Johns Hopkins School of Medicine Microbiome Forum. Dr. Johnson is a member of the advisory committee for a postdoctoral fellow at the school who recently received a large federal grant to study the effect on colon cancer of densely packed bacteria called biofilms. The scholar plans a visit to Dr. Johnson’s lab in the new year to learn more about metabolomics.

Next steps beyond the current study will involve comparing the colon cancer samples with healthy controls collected during a colonoscopy. Ultimately, targeted investigations to discover and then disrupt a pathway that leads to right-sided colon cancer in women could lay the groundwork for developing new therapeutics and interventions.

Possible treatments include antibiotics that eliminate an identified type of disease-causing bacteria or enhanced prevention methods through diet and lifestyle.

“We have learned so much already,” Johnson said. “I’m excited and optimistic for where this work will lead.”

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Submitted by Carissa R Violante on December 10, 2018