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. 2025 Jun;14(12):e71009.
doi: 10.1002/cam4.71009.

Impeding Quorum Sensing Among the Intestinal Microbiota Impacts the Metastatic Rate of Colorectal Cancer

Matthew Dietz  1   2 , Travis J Gates  1   3 , Rakesh Sikdar  2   4 , Subbaya Subramanian  1   3   5 , Mikael H Elias  2   4 , Christopher Staley  1   2   5
Affiliations

Impeding Quorum Sensing Among the Intestinal Microbiota Impacts the Metastatic Rate of Colorectal Cancer

Matthew Dietz et al. Cancer Med. 2025 Jun.

Abstract

Background: The gut microbiota is associated with colorectal cancer (CRC) risk and CRC metastatic potential. However, the role of bacteria in CRC progression and metastasis remains unclear.

Aims: Here, we hypothesized that microbial communication, mediated through quorum sensing (QS), was a critical component regulating microbial functions related to cancer progression and metastasis.

Materials & methods: To test this, male and female C57BL/6 mice were injected with organoids modeling aggressive colon cancer (CRC), carrying mutations in Apc, Kras, p53, and Smad4. Two groups of mice were treated with two different quorum quenching (QQ) lactonases (GcL or SsoPox) for 8 weeks (n = 10/group/sex). Fecal samples were collected weekly and characterized by Illumina next-generation sequencing, with tissues collected during necropsy.

Results: Male mice treated with SsoPox had fewer metastases than control mice (χ2 = 3.206, p = 0.073), with no SsoPox-treated male developing a metastasis. In contrast, female mice treated with SsoPox had more metastases than control mice (χ2 = 2.554, p = 0.110), and every female, SsoPox-treated mouse that developed a primary tumor also developed metastasis by the experimental endpoint. However, QQ treatment was shown to minimally affect the gut microbiome composition. Similarly, no significant differences were observed in inflammatory response as assessed by immunofluorescent staining or fecal concentrations of immunoglobulin A, calprotectin, or lipocalin-2. Differences in fecal short-chain fatty acid concentrations also did not differ significantly.

Discussion: These results suggest that QQ treatment has a sex-based effect on CRC metastatic rate.

Conclusion: Targeting communication among the gut microbiome may be a promising avenue for the development of CRC therapies that minimally impact microbial community composition and host immune response.

Keywords: autoinducer; microbiome; organoid; quorum quenching; signaling.

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Conflict of interest statement

M.H.E. is a co‐founder, a former CEO, and an equity holder of Gene&GreenTK, a company that holds the license to WO2014167140 A1, FR 3068989 A1, FR 19/02834. M.H.E. has filed the patents EP3941206 and WO2020185861A1. M.H.E.'s interests with Gene&GreenTK have been reviewed and managed by the University of Minnesota in accordance with its conflict‐of‐interest policies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Bar graph of male (A) and female (B) disease progression at the time of necropsy. One male SsoPox mouse died from complications of organoid injection. One female SsoPox mouse developed a blockage at week three that required euthanasia.
FIGURE 2
FIGURE 2
Principal coordinate analysis (PCoA) of male (A) and female (B) beta diversity on the day of organoid injection (DOS), end of week one (WK1), and experimental endpoint (END) for all treatment groups.
FIGURE 3
FIGURE 3
Principal coordinate analysis (PCoA) of beta diversity from colon (A and B) and tumor (C and D) samples in males (A, C) and females (B, D).
FIGURE 4
FIGURE 4
Immunofluorescent staining of CD206 (A–C), CD163 (D–F), and CD68 (G–I) found no significant differences between treatment groups in either males or females. Staining from control DW (A, D, G), GcL (B, E, H), and SsoPox (C, F, I) is shown.
See this image and copyright information in PMC

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