Name: Spyros Kremmydas
Title: The impact of EGF and IGF-Ι receptors’ inhibition on extracellular matrix modulation in 2D and 3D cancer cell cultures
Supervisor: Nikos K. Karamanos, Professor
Date: 02/06/2025
Time: 11:00
Zoom link: https://upatras-gr.zoom.us/j/96516568158?pwd=bbhcVOhnjiDkYcHAn8ZzQNxPCgnA5e.1
Among solid tumors, breast cancer (BC) remains the most frequently diagnosed cancer in women globally and the leading cause of cancer-related mortality in females. Triple-negative breast cancer
(TNBC) is a highly aggressive and heterogeneous BC subtype, which accounts for approximately 90% of BC-related deaths. Receptor tyrosine kinases (RTKs), including EGFR and IGF-IR, are crucial regulators of cell proliferation, survival, and differentiation, and their dysregulation has been closely linked to therapy resistance in TNBC. The inhibition of RTKs, using small chemical molecules or monoclonal antibodies, has emerged as a promising therapeutic strategy in previous years. However, recent research has shifted to the development of novel preclinical models that closely resemble the tumor microenvironment (TME). The development and progression of cancer are directly influenced by microenvironmental signals, including those from the extracellular matrix (ECM). Traditional two-dimensional (2D) cell cultures, while widely used in early preclinical studies, fail to replicate the structural and biochemical characteristics of TME three-dimensional (3D) nature. To this end, advanced 3D cell culture models that can simulate the growth and initial progression of solid tumors represent a promising approach.
The aim of the present study is to address this research gap by employing both 2D and spheroid-based 3D cell culture models to investigate the effects of EGFR and IGF-IR inhibition, individually and in combination, on two TNBC cell lines: Hs578T and shERβ MDA-MB-231 (ERβ-suppressed).
The results indicated that both EGFR and IGF-IR are key regulators of the functional properties in TNBC cells, such as cell proliferation and migration, as well as the expression of EMT markers and matrix metalloproteinases (MMPs). Using 3D spheroid-based models, additional functional properties like spheroid growth rate and dissemination were accessible for evaluation, with inhibition of both receptors leading to a reduction in treatment-dependent manners. Additionally, gene expression and functional properties of spheroid-derived cells were compared with their respective 2D cell cultures under treatment conditions. Interestingly, spheroid-derived cells of both cell lines exhibit different responses on their migratory capacity and on gene expression of MMPs and cell surface proteoglycans (PGs) upon inhibition of the two receptors. Conclusively, this dual-model approach underscores the importance of 3D systems in cancer research and provides new insights into RTKs’ regulatory role in TNBC.