The role of angiotensin signalling in peritumoral desmoplasia and lymph node metastasis: Implications for novel locoregional treatment approaches.

• Applicant: Dr. Benjamin Wolf
• Subject Area: Gynaecology and Obstetrics ; Anatomy and Physiology ; Hematology, Oncology ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 515493305

The goal of the proposed research project is to investigate the role of peritumoral desmoplasia in local and regional tumor spread in solid cancers. We have recently shown that peritumoral stromal remodelling (desmoplasia) is associated with a more aggressive tumor phenotype and inferior survival in cervical cancer patients. Specifically, we have found that the presence of desmoplasia is associated with lymph node metastasis and parametrial infiltration, two adverse prognostic characteristics of cervical cancer. However, the role of desmoplasia in gynecological cancers has not been studied in any depth. Therefore, the goal of the research project described here is to gain a better understanding of the mechanisms leading to the development of desmoplasia, and how desmoplasia might affect lymph node metastasis. Because no established non-human cervical cancer model exists, I will carry out the planned experiments in a pancreatic cancer mouse model. Pancreatic cancer displays a high degree of desmoplasia and metastasizes into regional lymph nodes similar to cervical cancer. Prof. Rakesh Jain (my host for the planned experiments) and his group have already desmonstrated that cancer associated fibroblasts orchestrate the development of desmoplasia and that they are affected by angiotensin signaling. Furthermore, losartan, an angiotensin receptor blocker, is able to reverse desmoplasia and improve treatment outcomes. Based on these findings, the research project is governed by the following two hypotheses: 1. Angiotensin signaling plays a central role in the development of peritumoral desmoplasia by reprogramming cancer associated fibroblasts. 2. Angiotensin signaling directly affects peritumoral invasion, lymphatic vessels and regional lymph nodes and thus contributes to lymph node metastasis. In the animal model, I will specifically investigate which tumor and peritumoral cells are affected by angiotensin signaling. For the first time, I will also focus on lymphatic vessels and regional lymph nodes and examine how the blockade of angiotensin signaling affects the risk of lymph node metastasis. The findings of the proposed research project will lead to a better understanding of the tumor microenvironment in desmoplastic cancer. As the tumor stroma is an important co-conspirator of malignant progression, the development of therapies targeting the tumor stroma in addition to cancer cells should be pursued beyond currently approved treatments, and my research findings will contribute to that goal. Blockade of angiotensin signaling to reverse desmoplasia seems to be a promising approach, and my research will help to further clarify the value of this strategy. It is my goal to transfer these findings to cervical and other gynecological cancers in the near future.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Rakesh K. Jain, Ph.D.