Charting the metabolic biogeography of the colorectum in cancer: challenging the right sided versus left sided classification

Abhishek Jain, Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, CT, 06510, USA.Follow
Montana T. Morris, Department of Surgery/Surgical Oncology, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.Follow
Domenica Berardi, Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, CT, 06510, USA.Follow
Trisha Arora, Omics Sciences Unit, EURECAT - Technology Centre of Catalonia, Avda. Universitat 1, Reus, 43204, Catalonia, Spain.
Xavier Domingo-Almenara, Omics Sciences Unit, EURECAT - Technology Centre of Catalonia, Avda. Universitat 1, Reus, 43204, Catalonia, Spain.
Philip B. Paty, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.Follow
Nicholas J. Rattray, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.Follow
Daniel Kerekes, Department of Surgery/Surgical Oncology, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA.Follow
Lingeng Lu, Department of Chronic Disease Epidemiology, Yale School of Public Health, 60 College Street, New Haven, CT06510, USA.Follow
Sajid A. Khan, Department of Surgery/Surgical Oncology, Yale School of Medicine, 333 Cedar Street, New Haven, CT, 06510, USA. sajid.khan@yale.edu.Follow
Caroline H. Johnson, Department of Environmental Health Sciences, Yale School of Public Health, 60 College Street, New Haven, CT, 06510, USA. caroline.johnson@yale.edu.Follow

Document Type

Article

Publication Title

Molecular cancer

Abstract

OBJECTIVE: Colorectal cancer (CRC) is conventionally classified as right sided, left sided, and rectal cancer. Clinicopathological, molecular features and risk factors do not change abruptly along the colorectum, and variations exist even within the refined subsites, which may contribute to inconsistencies in the identification of clinically relevant CRC biomarkers. We generated a CRC metabolome map to describe the association between metabolites, diagnostic and survival heterogeneity in cancers of different subsites of the colorectum. DESIGN: Utilizing 372 patient-matched tumor and normal mucosa tissues, liquid chromatography-mass spectrometry was applied to examine metabolomic profiles along seven subsites of the colorectum: cecum (n = 63), ascending colon (n = 44), transverse colon (n = 32), descending colon (n = 28), sigmoid colon (n = 75), rectosigmoid colon (n = 38), and rectum (n = 92). RESULTS: 39 and 70 significantly altered metabolites (including bile acids, lysophosphatidylcholines and lysophosphatidylethanolamines) among tumors and normal mucosa, respectively, showed inter-subsite metabolic heterogeneity between CRC subsites. Gradual changes in metabolite abundances with significantly linear trends from cecum to rectum were observed: 23 tumor-specific metabolites, 30 normal mucosa-specific metabolites, and 15 metabolites in both tumor and normal mucosa, had concentration gradients across the colorectum, and is disease status dependent. The metabolites that showed a linear trend included bile acids, amino acids, lysophosphatidylcholines, and lysophosphatidylethanolamines. Comparison of tumors to patient-matched normal mucosa revealed metabolite changes exclusive to each subsite, thereby further highlighting differences in cancer metabolism across the 7 subsites of the colorectum. Furthermore, metabolites associated with survival were different and unique to each subsite. Finally, an interactive and publicly accessible CRC metabolome database was designed to enable access and utilization of this rich data resource ( https://colorectal-cancer-metabolome.com/yale-university ). CONCLUSIONS: Gradual changes exist in metabolite abundances from the cecum to the rectum. The association between patient survival and distinct metabolites with anatomic subsite of the colorectum, reveals differences between cancers across the colorectum. These inter-subsite metabolic heterogeneities enrich the current understanding and substantiate previous studies that have challenged the conventional classification of right-sided, left-sided, and rectal cancers, by identifying specific metabolites that offer new biological insights into CRC subsite heterogeneity. The database designed in this study will enable researchers to delve into granular information on the CRC metabolome, which until now has not been available.

First Page

211

DOI

10.1186/s12943-024-02133-5

Publication Date

9-28-2024

Identifier

39342363 (pubmed); PMC11438248 (pmc); 10.1186/s12943-024-02133-5 (doi); 10.1186/s12943-024-02133-5 (pii)

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