Colorectal cancer (CRC) is the third most frequent tumor entity worldwide and the second leading cause of cancer-related death. Development of metastasis is a concern for patients and clinicians alike as metastasis may be fatal, causing mass-effect and meddling with homeostasis. Approximately 30% of CRC patients show metastasis already at diagnosis and another 25-30% of CRC patients develop metastasis metachronously. The molecular and cellular events during the process of metastasis are incompletely understood. Inflammation and immunity are important determinants of tumorigenesis, impacting cancer development from initiation, promotion, progression and metastasis. Germline-encoded pattern recognition receptors (PRRs) are among critical effectors of the inflammatory responses are that, upon sensing microbial- or danger-associated molecular patterns, elicit an inflammatory response to restore homeostasis. Therefore, the microbiome has emerged as a major regulator of colorectal carcinogenesis. Recently, we have shown that microbial-associated molecular patterns are able to regulate the expression of mucins and antimicrobial peptides specifically in cancer cells leading to either tumor barrier stabilization or tumor barrier breach at the luminal surface and exclusion or invasion of bacteria inside the tumors, respectively. This means that bacteria can regulate the tumor barrier independent from the intestinal barrier. Based on these findings, we hypothesize that the tumor barrier functionality and the microbiota are both involved in regulation of EMT and metastasis formation. We assume that two distinct mechanistic pathways are involved:
- metastasis initiation is regulated through induction of tumor barrier breach leading to a reorganization of tumor microenvironment (immunological, microbial and mesenchymal) which acts pro-metastatic.
- the tumor intrinsic microbiome is able to regulate not only tumor barrier function but also tumor cell plasticity and premetastic niche formation leading to EMT, invasion and metastasis
To this end, we will address the following questions in the third funding period (FP3):
- which signal transduction pathways and interactions between bacteria and tumor barrier breach are activated?
- how is the immunological, microbial and mesenchymal tumor microenvironment reshaped upon barrier breach to a pro-metastatic milieu?
- does barrier functionality influence tumor cell adhesion, tumor stiffness, EMT, tumor cell plasticity and premetastatic niche formation as critical functions of metastasis formation?
- how do certain bacteria species influence EMT and metastasis formation of colorectal cancer?