VEGF-C-dependent host-tumor interactions that promote metastasis in response to chemotherapy

• Applicant: Professor Dr. Jonathan Paul Sleeman
• Subject Area: Cell Biology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466381716

Chemotherapy and targeted anti-cancer drugs strongly restrict or reverse tumor growth. However, the response of host tissue to therapy can counteract the anti-tumor activity of these therapies by promoting tumor re-growth and/or metastases, thus limiting their efficacy. We have previously identified greatly increased VEGF-C expression, both locally and systemically, as one such host response to paclitaxel (PTX) chemotherapy. This leads to increased tumor neo-lymphangiogenesis that supports metastasis. We found that VEGFR-3, the main receptor for VEGF-C, is expressed on the surface of chemotherapy-activated macrophages. Its expression contributes to lymphangiogenesis largely by promoting the secretion of proteases such as cathepsins, which leads to increased heparanase activity and increased VEGF-C expression. We also demonstrated that upregulation of systemic VEGF-C induces the recruitment of CD11b+/Ly6G+ neutrophils to the lungs, which suffices to induce metastasis formation. The observation that the VEGFR3/VEGF-C axis promotes metastasis to the lung by recruiting immune cells is remarkable. However, the cellular and molecular mechanisms downstream of this axis are unknown. The broad aim of this proposal is to dissect the cellular and molecular pathways through which increased systemic VEGF-C induces chemoresistance and metastasis. Specifically, we aim to (i) determine the response of pulmonary macrophages increased systemic VEGF-C and their crosstalk with neutrophils; (ii) evaluate the contribution of PTX-educated myeloid cells to ECM remodeling and tumor cell seeding in the lung, and the role of ECM remodeling enzymes in this process; (iii) examine whether the mechanisms of PTX-induced metastasis are shared with other chemotherapies. This study will provide new insights into the fundamental mechanisms through which VEGF-C-VEGFR3 signaling fosters the development of metastasis-promoting organ microenvironments following exposure to chemotherapy. The long-term goal of this study is to develop novel ways of blocking pro-tumorigenic and pro-metastatic host responses to chemotherapy, thereby increasing the efficacy of current treatment modalities.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professor Dr. Yuval Shaked