AIRC: IG 2018 ID 21372 - Dynamic signaling reciprocity shapes invadopodia function and metastatic process of ovarian cancer: role of endothelin-1 (DSB.AD001.181)

Thematic area

Biomedical sciences

Project area

Structure responsible for the research project

Institute of molecular biology and pathology (IBPM)

Project manager

LAURA ROSANO
Phone number: 0649933874
Email: laura.rosano@uniroma1.it

Abstract

The invasion of high-grade serous ovarian cancer (HG-SOC) cells through the basement membrane and interstitial matrix involve the formation of actin-based protrusions, invadopodia, capable to spatially concentrate the ECM proteolytic degradation, facilitating cell invasion. Growth factor receptors might engage integrins and associated proteins to coordinate invadopodia activity. These processes are influenced by dynamic reciprocity of cancer and stromal cells and hypoxic cue, which will feedback and further stimulate mechanosignaling. In the G-Protein Coupled Receptor (GPCR) family, the receptor A (ETAR) for endothelin-1 (ET-1) drives HG-SOC invadopodia, invasion and metastasis through the scaffolding function of ²-arrestin1 (²-arr1). However, how ETAR relates to integrins and stromal elements to operate invadopodia is unexplored. We hypothesize that ET-1R/²-arr1 synergizes with integrin signaling to fine-tune signal reciprocity between tumor and stromal cells, such as fibroblasts and mesothelial cells, priming HG-SOC cells for metastatic colonization.

Goals

This project aims to:
1. To obtain a preclinical platform of patient-derived (PD) primary cells for developing 3D cultures, 3D organotypic models and PDXs.
2. Investigate the interaction between of ET-1R and integrin ²1 (Int²1) signalling in invadopodia function.
3. Evaluate the ET-1R/Int²1 interaction as a mediator of the dialogue between cancer and stromal cells, which can be amplified in the hypoxic environment, affecting invadopodium function.
4. Develop organotypic models as a tool to assess the feasibility of new therapeutic strategies based on the modulation of the activity of ETAR and Int²1.
5. Explore the co-targeting ET-1R and Int²1 as a potential drug combination for HG-SOC treatment in patient-derived xenografts, to translate these discoveries into cancer treatment directed at vulnerabilities in the TME to prevent cancer dissemination.
6. Evaluate the expression of ET-1R/²-arr1/Int²1 and related effectors in HG-SOC specimens to validate this signature as a potential novel biomarker of metastasis.

Start date of activity

02/01/2021

Keywords

cancer, metastasis, 3D models

Last update: 03/01/2025