Unraveling the Metabolic Landscape of Colorectal Cancer

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

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

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

“Our findings indicate a continuum in changes to metabolite concentrations, which underscores the need for a more nuanced classification of CRC beyond the simplistic right-versus-left-side dichotomy,” said Johnson, an associate professor of epidemiology (environmental health sciences) at YSPH, a member of the Yale Cancer Center, and one of the study’s senior authors.

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

One of the key revelations of the study is the gradual changes in metabolite abundances observed from cecum to rectum, rather than abrupt shifts at anatomic boundaries.

The research revealed that metabolites such as bile acids, amino acids, lysophosphatidylcholines (lysoPCs), and lysophosphatidylethanolamines (lysoPEs) exhibited linear trends across the colorectum, dependent on disease status, said Khan, an associate professor of surgery (oncology) at the 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 length of the colon, which may influence tumor behavior and patient outcomes," explained Jain, an associate research scientist in Johnson’s lab and the study’s lead author.

The metabolome map developed from the study offers a valuable resource for furthering 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 distinctly across the subsites.

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

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

"In creating this database, we aim to provide a powerful tool for researchers and clinicians to explore CRC's metabolic intricacies, ultimately guiding more targeted and effective interventions," Johnson said.

The insights from this study have significant implications for the future of CRC research and treatment. Moving beyond conventional classifications could enhance 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 how we approach cancer care in surgical oncology, medical oncology, and gastroenterology, from early detection to personalized treatment strategies,” said Khan.

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

“Our findings lay a robust foundation for future investigations aimed at deciphering the underlying biological mechanisms driving subsite-specific differences in CRC,” Jain said.

Researchers from Memorial Sloan Kettering Cancer Center in New York, the Technology Centre of Catalonia in Spain, and the Strathclyde Institute of Pharmacy and Biomedical Sciences in the United Kingdom contributed to the study.