Addressing contamination and detection challenges in low-biomass samples identifies tumor-associated microbiota in colorectal cancer metastases
(2026)
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- Abstract
- Metastatic colorectal cancer (mCRC) remains one of the main causes of cancer mortality worldwide, despite significant advances in molecular oncology and personalized medicine. The biological mechanisms driving metastatic dissemination, therapeutic resistance, and disease heterogeneity are only partially understood, highlighting the need for new conceptual frameworks to complement current genetic and immunological models of cancer progression. In parallel, the growing understanding of the human microbiome has profoundly transformed modern biomedical research. Microbial communities are now recognized as major regulators of host metabolism, inflammation, and immunity, thereby influencing the onset, progression, and treatment response of numerous diseases, including cancer. While the intestinal microbiome has been increasingly acknowledged as a key modulator of tumor behavior and therapeutic efficacy, the idea that bacteria may also reside within tumor tissues themselves has only recently emerged. This field, referred to as tumor microbiome research, remains largely unexplored and debated. Its investigation presents specific challenges related to the very low bacterial biomass in tissues and the high risk of contamination at each experimental step, requiring rigorous methodological control and analytical precision. This thesis focuses on the characterization of the tumor-associated microbiota in mCRC and on the establishment of methodological standards enabling its reliable study. The introductory chapters present the clinical and biological context of mCRC and its potential interplay with the tumor- associated microbiota, provide a concise overview of current knowledge on the human microbiome, and discuss the conceptual and technical controversies surrounding bacterial detection in tumors. They also emphasize the need for standardized, contamination-aware strategies in low-biomass microbiome research. The results chapters describe the work leading to the submitted manuscript, detailing the development of a multi-cohort, multi-control framework designed to rigorously evaluate microbial presence in frozen tumor samples. Each analytical step, from tissue collection and documentation to bioinformatic decontamination, is presented in detail. This framework was applied to a large set of CRC and non-CRC samples to assess bacterial presence and distribution across primary and metastatic sites, demonstrating that reproducible microbial signals can be detected in low-biomass tumors under tightly controlled conditions. The final discussion integrates these findings into a broader reflection on their biological significance, clinical implications, and methodological contributions, while acknowledging the study’s limitations. It outlines perspectives for future mechanistic and translational research and underscores the importance of harmonizing analytical standards. Overall, this work positions the tumor-associated microbiota as a promising and previously unexplored component of the tumor microenvironment, particularly in mCRC, offering new conceptual bridges between microbial ecology, oncology, and precision medicine.
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Stevens, P. (2026). Addressing contamination and detection challenges in low-biomass samples identifies tumor-associated microbiota in colorectal cancer metastases. https://hdl.handle.net/2078.5/273829