Exosome-mediated crosstalk between colorectal cancer and tumor microenvironment: impact on tumor progression and dissemination

• Applicant: Professor Dr. Christoph Kahlert
• Subject Area: General and Visceral Surgery
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 394479784

Exosomes are small microvesicles (50 to 150 nm) that can shuttle active microRNAs, mRNAs, DNA fragments and proteins from a donor cell to recipient cells. By this mechanism, tumor cells can manipulate the local and systemic microenvironment to aid in cancer growth and dissemination. While recent studies have shown that the education of the microenvironment in distant organs supports colonization of metastasis-initiating cells in pancreatic cancer, breast cancer or melanoma, the effect of tumor-derived exosomes for tumor dissemination in colorectal cancer remains still unclear. Therefore, in Aim1.1 of our proposal, we want to investigate, if tumor-derived exosomes promote the formation of a premetastatic niche in colorectal cancer. To approach this goal, will perform in vitro and in vivo experiments to assess if exosomes from highly metastatic human and murine cell lines evoke a different activation response in recipient fibroblasts in comparison to low-metastatic human and murine cells. The results will amend our understanding if the exosomal uptake and organ-specific distribution differs between metastatic and non-metastatic colorectal cancer cell lines. To further determine if tumor-derived exosome support the formation of metastasis, we will block exosome secretion in human and murine colorectal cancer cells endogenously by knockdown of Rab27a or exogenously by the chemical inhibitor GW4869 or by heparine. We expect that the inhibition of endogenous and exogenous release/uptake of exosomes will reduce metastasis. Moreover, we hypothesize that the impairment of metastasis by blocking exosome release will be accompanied by a decreased activation pattern of the stromal tissue. In Aim1.2 we want to evaluate if tumor-derived exosomes from metastatic and non-metastatic cancer cells can determine organotropism in colorectal cancer. Moreover, we aim to identify exosome-associated molecules that can increase metastasis. Subsequently, we will investigate if targeting those specific exosomal markers can reduce (organotropic) metastasis. In Aim 2, we want to elucidate the role of the exosomal crosstalk between fibroblasts and tumor cells. This is a novel concept since up-to-date, the majority of the studies has focused only on the role of the unidirectional exosomal transfer from tumor cells on fibroblasts. These data can provide a new perspective of the exosome-mediated metastatic cascade and will further assess the role of the tumor microenvironment on tumor progression in colorectal cancer. The results of Aim 1 and Aim 2 will help to identify potential diagnostic and predictive markers, which we plan to validate in a large cohort of patients with colorectal cancer in Aim 3. These data would provide a novel approach to stratify patients into different risk categories and to improve the diagnosis for the early detection of recurrent colorectal cancer.

• DFG Programme: Research Grants