Molecular Signatures for Microbe-Associated Colorectal Cancers.

Area of Science:

• Oncology
• Microbiology
• Genetics

Background:

• Colorectal cancer (CRC) development involves genetic factors and microbial imbalances, but the role of infections in initiation is unclear.
• Rising CRC incidence necessitates precise identification of early events, prompting investigation into microbial and host genetic influences.

Purpose of the Study:

• To construct a network model identifying continuum states during CRC initiation from normal tissue to pre-cancerous lesions.
• To examine the influence of microbes and host genetics on early CRC events.
• To identify a Microbe-Associated Colorectal Cancer Signature (MACS) and validate its role in CRC initiation.

Main Methods:

• A Boolean network model was developed using transcriptomic data from healthy and adenoma patients.
• Focused on *Fusobacterium nucleatum* (Fn) as a model CRC-associated microbe.
• Validated MACS-associated genes and proteins in genetically predisposed mouse organoids and patient-derived organoids (PDOs) using RT-qPCR, RNA seq, ELISA, IF, and IHCs.

Main Results:

• Identified a MACS upregulated in adenomas, comprising CLDN2, LGR5, CEMIP, and IL8.
• MACS induction was specific to *Fn* infection and heightened in genetically predisposed organoids.
• MACS expression in PDOs correlated with known CRC lifetime risk.

Conclusions:

• Computational prediction and organoid validation identified early CRC initiation events.
• MACS highlights that CRC-associated microbes increase risk in genetically predisposed hosts.
• MACS shows potential for CRC risk prediction and targeted cancer prevention strategies.