Daniela Elena Costea

Daniela Elena Costea has an education in dentistry (1991–1997) and oral pathology (2006), with a PhD in oral sciences from 2005. She has been conducting research in epithelialmesenchymal interactions in normal tissues and carcinoma since 2000. She has been a professor in tumor pathology at the Medical Faculty, University of Bergen (UiB) since 2013 and carries out surgical pathological diagnostic pathology in oral and ear-nose-throat areas since 2011. She served as a representative for the UiB in the Board of the Norwegian Cancer Association Norway and is Chair of the Scientific Advisory Board, National Institute for Cancer Research, Czech Republic. She has been PI or co-PI of several national and EU-funded grants.

Brief group presentation and history

Costea’s group was established in 2011 with a grant awarded in 2010 to Costea from the Bergen Medical Research Foundation.

Research Focus

Research in Costea’s group is focused on tumor-stroma interactions for the identification of tumor microenvironment-related prognostic biomarkers in mucosal squamous cell carcinomas. The group is developing relevant experimental models that are sufficiently elaborated to mirror the complex in vivo tumor microenvironment, yet feasible enough for individual analysis and modulation of its different components. The aim is to reveal cancer associated fibroblasts’ (CAFs) respective contribution to drug resistance and tumor progression.

Subprojects and Most important results

1. Mechanisms of tumor-stroma (fibroblasts) interactions

Costea’s group has demonstrated that interactions between carcinoma cells and surrounding fibroblasts occur first at the metabolic level, before fibroblasts are induced into CAF activated phenotype and senescence by cancer cells. The major and novel finding was the observation that normal neighboring fibroblasts are induced to export mitochondria towards carcinoma cells through both direct contact and by indirect mechanisms (Zhang Z et al., Cell Mol Life Sci. 2020). Furthermore, the group’s studies showed that while metformin (newly proposed as adjuvant for head and neck squamous cell carcinoma — HNSCC) could significantly inhibit cell growth and induce apoptosis of cancer cells, its effects on cancer cells are annihilated when CAFs are present through inhibiting AMPK and PARP activity, maintaining mitochondrial membrane potential, and increasing oxidative stress (Zhang Z et al., Cell Cycle, 2019).

2. Stroma as a source of prognostic biomarkers

The group’s transcriptomic studies showed molecular evidence for the existence of at least three subgroups of CAF in HNSCC, and functional evidence for a protumorigenic role of two of the three CAF subgroups. This was a major finding and one of the first papers pointing towards the heterogeneity of CAF in the tumor microenvironment (Costea et al., Cancer Res 2013). A subsequent global miRNA array study identified twelve differentially expressed miRNAs. One of these, miR-204, had a tumor-suppressive function through inhibition of fibroblast migration by modulating expression of several motility-related molecules (Rajthala S et al., Int J Mol Sci. 2021). It was shown, for the first time, that miR-204 targets integrin α11, a collagen I receptor that has been involved in cell motility and showed previously to be specifically upregulated in CAFs. For further phenotypical characterization of CAFs at the protein level and elucidation of CAF heterogeneity, imaging mass cytometry was applied (Tornaas S et al., Heliyon. 2024).

3. Establishing novel, more representative human-based models in carcinoma research

In collaboration with Line Bjørge’s group, the Costea group established novel cell lines from mucosal carcinomas. Of note is a unique cell line developed from a vulva cancer patient with lichen atroficus et sklerosus, the first isolated cell line of this type (Dongre H et al., Exp Cell Res, 2020).

4. Development of point-of-care cancer diagnostic tools for use in resource poor settings

Oral cancer is increasing at an alarming rate, particularly in low-income countries. This urges for research into noninvasive, user-friendly diagnostic tools that can be used in limited-resource settings. The Costea group tested and validated the feasibility of e-nose technology for detecting oral cancer in the limited-resource settings of the Sudanese population, where it offers a valuable cost-effective strategy to tackle the burden posed by oral squamous cell carcinoma (OSCC) (Mohamed N et al., Healthcare. 2021).

Translational, clinical and societal importance

• The Costea group identified a number of genes/miRNAs significantly dis-regulated in CAFs. Integrin α11 and mir204 are further investigated for their prognostic marker value.
• Costea’s results indicate that metformin effects on cancer cells are modulated by the microenvironment and that this must be taken into consideration in the context of developing new combination of drugs including metformin for cancer treatment.
• The group is providing robust experimental tools to the research community. In collaboration with the Bergen Technology Transfer Centre (VIS), they made available some of their cell lines through the CRUK-related company Ximbio and are now in process of a establishing their own spin-off UiB-related company for commercialization of their own isolated and characterized cell lines and 3D models.
• The results of the e-nose study provide data to substantiate proposing this device as a feasible solution for oral cancer screening in resource-limited areas where OSCC poses a major burden of disease.

Future perspectives from 2024

The Costea group will continue their biomarker discovery studies by deep tissue profiling of comprehensive signatures of distinct CAF niches, as well as the niches’ relationship with each other and other components of the microenvironment in clinical cohorts of head and neck and vulva carcinoma. Costea also plans to translate the group’s laboratory findings on the tumor-stroma interactions and recently identified key involved molecules towards clinical use, as both prognostic biomarkers in prospective trials for better stratification of patients and for development of more personalized therapies that target both cancer cells and their microenvironment.

They are also developing in vitro multicellular models as “avatars” for vulvar and oral cancers for testing the concept of “trial in a dish” for these cancers.