Daniela Elena Costea
Professor Daniela Elena Costea and her team in the Experimental Pathology Research Group are focusing on understanding the role of epithelialmesenchymal interactions in carcinoma progression and identification of micro-environment-related prognostic biomarkers.
1. Mechanisms of tumor-stroma interactions including metabolic coupling.
2. Understanding the role of tumor stroma in drug resistance.
3. Stroma as a source of prognostic biomarkers.
The Costea group has shown, for the first time, that carcinoma cells are able to induce a unidirectional mitochondrial exchange from normal neighboring fibroblasts (Zhang et al, Cell Mol Life Sci, 2019), in addition to increased L-lactate production and oxidative stress via induced hypoxia, mitophagy and mitochondrial permeability transition pore opening, leading to their metabolic re-programming. These metabolic alterations can be further exploited for metabolically addressed targeted therapy towards the stromal tumor compartment. Of particular interest is that the group showed that the metabolic reprogramming of the fibroblasts occurs before their activation and conversion into a carcinomaassociated (myo)fibroblast phenotype and was not accompanied by cellular senescence.
Another novel finding was that the metabolically reprogrammed neighboring fibroblasts were able to rescue carcinoma cells from the metformin-induced apoptosis through inhibiting the activity of AMPK and PARP, maintaining mitochondrial membrane potential and increasing the oxidative stress (Zhang et al, Cell Cycle, 2019). The results indicate that metformin effects on cancer cells are modulated by the microenvironment, and this must be taken into consideration in the context of developing a new combination of drugs for cancer treatment including metformin.
Together with the research group of Professor Line Bjørge, the Costea group has established novel experimental models of vulvar carcinogenesis and revealed that also in this cancer type, the stromal fibroblasts play a key role for tumor progression (Dongre et al, Exp Cell Res, 2019).
The group’s results point towards complex interactions between carcinoma cells, carcinoma associated fibroblasts, immune cells and endothelial cells. The challenge is how to decipher these interactions and what experimental models should be used and established that are sufficiently elaborated to mirror the complex in vivo tumor, but feasible enough for individual analysis and modulation of its different components in order to reveal their respective contribution to drug resistance and tumor progression.
The group’s core activities will continue towards understanding the tumor-stroma interactions, and how they can be used for personalized therapy. The focus will be on deeper characterization of the fibroblast heterogeneity and how this differentially influences tumor progression and drug resistance in HPV positive and negative cancers.