Elucidating the role of microbiota-driven “Tumor-elicited inflammation” in colorectal cancer progression

• Applicant: Dr. Sophia Chikhladze
• Subject Area: General and Visceral Surgery
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 442076297

Colorectal cancer (CRC) is the third most common cancer worldwide and the leading cause of cancer mortality. In 2014, over 60.000 new colorectal carcinoma cases were diagnosed in Germany and over 24,000 cancer deaths were reported. The majority of these deaths are caused by metastatic relapse. Inflammation seems to have an important role in colorectal cancer prognosis. Presence of certain chemokines, cytokines and myeloid cell subsets correlates with poor prognosis in CRC. CRC tumors after their formation induce frank inflammatory reaction termed “Tumor-elicited inflammation” (TEI). The mechanisms of TEI in CRC, especially in CRC malignant progression, are unknown. Important and unresolved questions include: 1) What are the tumor-specific signals, which activate TEI? 2) What are molecular and cellular mechanisms of TEI action? 3) How does TEI promote CRC invasion and metastasis? The colon is rich in microbes and hypothetically, bacterial products are excellent candidates for TEI induction. We will examine to which extent microbiota influence/control CRC progression. Here, we will establish parameters of tumor-adherent microbiota and of cellular types involved in TEI. We will define how individual microbiota and inflammatory states affect cancer growth and metastasis. We will further explore in a reductionist mouse model how differences in microbiota-driven intratumoral immune responses influence murine CRC. We will further identify tumor-associated bacteria in human CRC and explore their relevance. We will calculate and interpret correlations between overall survival and the aforementioned parameters, which potentially reflect a role of tumor mucosa adherent microbes and TEI in resistance to anti-cancer therapy. We expect that chemotherapy-treated patients with higher abundance of adherent microbes and enhanced expression of TEI inflammatory genes will demonstrate earlier clinical relapse, harboring tumors with enhanced proliferation and with a “pro-tumorigenic” environment increased numbers of myeloid cells and a lack of activated cytotoxic T cells. This work will allow the creation of a prediction tool for metastatic relapse and resistance to therapy, based on microbiota and TEI responses.

• DFG Programme: Research Fellowships
• International Connection: USA
• Participating Person: Sergei Grivennikov, Ph.D.