Role of H19 and the mir-675 in breast cancer tumor development and development of brain metastasis
Résumé
Through the past 5 years, we published 66 research papers, including 24 in collaboration with national and international teams. Seventeen PhD students, within the laboratory and in collaboration with international teams (Italy and Japan), successfully defended their PhD, and pushed forward their career in academics postdoc fellow or in the private sector. Also, the team was joined in 2020 by 2 researchers, Roland Bourette, CNRS researcher, and Dimitra Gkika, assistant researcher at the university of Lille (UL). Later on, Dimitra got promoted to full Professor position at UL in 2022. The research of our “Cell plasticity and Cancer” team has been focused on breast cancer, and specially on the triple negative subtype (TNBC). We have 3 main topics of research to decipher the role of specific cell signaling or cell phenotypes in (1) resistance, (2) persistence and (3) metastasis, using various models as cell lines, 3D cultures, organ-on-Chip (OoC) and preclinical models.
In this context, our research has focused on unraveling the signaling pathways triggered by NGF and its precursor, proNGF, in TNBC. We revealed that NGF's interaction with TrkA leads to the formation of a complex with the CD44v3 only (Trouvilliez et al., J Exp Clin Can Res, 2022), playing a crucial role in metastasis while driving LOXO-101 ineffectiveness (Trouvilliez et al., in prep.). Furthermore, proNGF induces the formation of a different complex involving TrkA and EphA2 (Lévêque et al, Cancer Lett., 2019), which is also implicated in brain metastasis (Cicero et al, Exp Hematology & Oncology 2023).
We have investigated the role and relative contribution of the long non-coding RNA H19 and its miRNA in cancer phenotypes, especially in triple-negative cancers. While both H19 and miR-675 increase proliferation, migration, invasion, clonogenicity, and the development of stem-like characteristics in breast cancer cells, they have opposite roles in epithelial-mesenchymal transition (EMT) (Peperstraete et al., Cancers 2020).
Also, wes established persistent triple-negative breast cancer (TNBC) cell models by treating MDA-MB-231 and SUM159-PT TNBC cell lines with chemotherapy for 18 weeks. Chemo-persistent cells were more proliferative and less sensitive to chemotherapeutic drugs, particularly in the case of MDA-MB-231 cells. The study suggests that targeting mitochondrial pyruvate metabolism may help overcome the adaptive changes observed in chemo-persistent TNBC (Winter et al., Neoplasia 2023). Additionally, the research identified COL1A1 as a potential therapeutic target for preventing brain metastasis formation in chemo-persistent TNBC cells (Submitted).
Looking at the dynamic plasticity of cancer cells under stress, we developed a CSC reporter, based on transcriptomic analysis to identify, track and characterize cancer stem cells (CSC) (Bidan et al., Proteomics 2019). Interestingly, we could show that CSC are better equipped to transmigrate through an endothelial using OoC device. This reporter has been shared with several teams around the world on request. To further study the CSC plasticity, we have identified specific DNA methylation modification. Along the way, we had to develop a specific R-Based software, which is now licensed under GPL-3.0 license (Denoulet et al., Bioinformatics 2023).
To strengthen our research projects, we’ve been joined by Dr. Bourette and Pr. Gkika. He established 2 murine models of tumorigenesis. He has first used them to investigate a marker for breast cancer stem cells (Tian et al. Stem Cell Reports 2019). The second part has involved studying the gene program of chemoresistance associated with this reporter. Pr. Gkika established 2 research axes on the role of ion channels in oxidative stress and metabolism during the progression of triple-negative cancers in cancer cells and endothelial cells.
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