Metabolic map of colorectal cancer challenges conventional disease classifications

A new study from the Yale School of Public Health (YSPH) offers new insights into our understanding of colorectal cancer (CRC) that challenge conventional classifications of the right and left sides of the disease.

The location of a tumor, whether on the right or left side, can have a significant impact on prognosis and survival. Left-sided tumors are more common and easier to detect than right-sided tumors, which are associated with a poorer prognosis and lower survival rate.

The new research, led by Abhishek Jain, Caroline Helen Johnson, and Dr. Sajid A. Khan, MD, produced the first comprehensive map of the CRC metabolome, revealing distinct metabolic profiles along various subsites of the colorectum. The findings could pave the way for more precise diagnostics and treatments tailored to the metabolic environments of each tumor.

“Our results indicate a continuum of changes in metabolite concentrations, highlighting the need for a more nuanced classification of CRC beyond the simplistic right-left dichotomy,” said Johnson, associate professor of epidemiology (sciences of Environmental Health) at YSPH, a member of the Yale Cancer Center and one of the lead authors of the study.

The study, published in the journal Molecular cancerused liquid chromatography-mass spectrometry to analyze the metabolic profiles of 372 tumor tissues and normal mucous membranes corresponding to seven subsites of the colorectum: the cecum, the ascending colon, the transverse colon, the descending colon, the sigmoid colon, the rectosigmoid colon and the rectum. The researchers identified 39 metabolites significantly altered in tumors and 70 in normal mucosa across regions, revealing considerable metabolic heterogeneity between subsites.

Gradual metabolic changes

One of the main revelations of the study concerns the gradual changes in metabolite abundance observed from cecum to rectum, rather than abrupt changes at anatomical boundaries.

The research found that metabolites such as bile acids, amino acids, lysophosphatidylcholines (lysoPC) and lysophosphatidylethanolamines (lysoPE) showed linear trends in the colorectum, depending on the disease state, Khan said, associate professor of surgery (oncology) at Yale School. of Medicine, a member of the Yale Cancer Center and co-senior author of the study.

“This continuum suggests that metabolic processes do not change abruptly but rather evolve along the colon, which may influence tumor behavior and patient outcomes,” explained Jain, a research associate in Johnson’s lab and senior author. of the study.

Benefits of a metabolome map

The metabolome map developed from the study offers a valuable resource to further our understanding of CRC biology. The map details metabolite changes unique to each colorectal subsite, highlighting differences in cancer metabolism that can significantly affect diagnostics and treatment strategies. Notably, some metabolites were linked to patient survival rates, varying markedly across subsites.

For example, lysoPC and lysoPE levels demonstrated subsite-specific variations, being significantly upregulated in tumors from the sigmoid, rectosigmoid, and rectal regions, unlike other subsites. Similarly, LysoPC (20:3) was associated with poor survival, particularly in colon descending tumors. This knowledge highlights the importance of considering subsite-specific metabolic profiles in the clinical management of CRC, Khan said.

Public Metabolome Database

To promote broader use and exploration of the rich data generated, researchers designed a publicly available CRC metabolome database. This interactive platform allows users to delve into detailed metabolite distributions across CRC subsites, facilitating hypothesis generation and providing insights into the metabolic underpinnings of CRC.

“By creating this database, we aim to provide a powerful tool for researchers and clinicians to explore the metabolic intricacies of CRC, ultimately guiding more targeted and effective interventions,” Johnson said.

Implications and future directions

The insights from this study have significant implications for the future of CRC research and treatment. Going beyond conventional classifications could improve the accuracy of biomarker identification and improve the specificity of therapeutic approaches.

“Understanding the metabolic heterogeneity of CRC at such a granular level could transform the way we approach cancer care in surgical oncology, medical oncology and gastroenterology, from early detection to personalized treatment strategies,” he said. Khan said.

This study not only validates the existence of a metabolic continuum along the colorectum, but also paves the way for further research into how these metabolic differences influence tumor development and patient survival, the researchers said. authors.

“Our results provide a solid basis for future investigations aimed at deciphering the underlying biological mechanisms driving subsite-specific differences in CRC,” Jain said.