Functional characterization of the colorectal cancer metastasis microbiome

Introduction

Host cells and microbial inhabitants form an intricate ecosystem in the human body, extensively influencing host phenotypes in health and disease. Despite much progress in sequencing-based cancer microbiome research, elucidating functional roles of bacteria in metastasis formation remains an important unsolved challenge. In the METABAC project, we will explore such bacterial roles as drivers of colorectal cancer metastasis. We will investigate new concepts on whether bacteria can equip cancer cells with malignant features, migrate within the host, and potentially represent targets for cancer therapy.

Aim 1: Characterization of Microbial Inhabitants

In Aim 1, my group will characterize the microbial inhabitants of colon tumors and metastases. We will uncover bacterial species and their genetic features in metastases by using:

• Sequencing-based approaches
• Imaging-based approaches
• Culturing-based approaches

Aim 2: Mechanistic Dissection of Bacterial Impacts

In Aim 2, we will mechanistically dissect functional impacts of metastasis-derived bacteria on distinct stages of the metastatic process. For this, we will use specialized platforms that we have pioneered, including:

1. Organoid platforms
2. Organ chip platforms
3. Orthotopic organoid-bacteria co-engraftment platforms

Aim 3: Bacterial Migration and Tropism

In Aim 3, uncovering the tropism, timing, and routes of bacterial migration to different metastasis sites takes center stage. Bacterial strains and organoids derived from different metastasis sites will be co-engrafted into mice and traced to:

• Lymph node metastases
• Liver metastases
• Lung metastases

Conclusion

The METABAC project will provide an unprecedented characterization of microbial roles in metastasis. Our combination of metastasis-derived bacterial strains with novel organoid, organ chip, and in vivo platforms puts us in a unique position to close the gap between cancer microbiome sequencing and mechanistic studies and promises groundbreaking functional insights into host-microbe interactions in cancer and beyond.