Investigating tumor cell motility under hypoxia and therapeutic resistance in cancer models
Surguta Sára Eszter
Pathological and Oncological Divison
Dr. Matolcsy András
Országos Onkológiai Intézet, Konferencia terem, 1-es épület, 1. emelet
2025-05-05 14:00:00
Molekuláris és experimentális onkológia
Dr. Bödör Csaba
Dr. Tóvári József
Dr. Balázs Margit
Dr. Szász Attila Marcell
Dr. Benyó Zoltán
Dr. Lotz Gábor
Dr. Jurányi Zsolt
We investigated two critical aspects of cancer biology. The effects of hypoxia on lung ade-nocarcinoma cell motility as referred to the metastasis formation and the mechanisms of ac-quired resistance to BRAF inhibitors in melanoma. Regarding hypoxia, we observed cell-line-specific and time-dependent effects on the migratory activity of the lung adenocarcinoma cells. Notably, hypoxia either maintained or slightly reduced cellular proliferation. Interestingly, the hypoxia-mimicking agent CoCl2 failed to replicate the effects of true hypoxic conditions on sin-gle-cell motility. We found that invasion under confluent conditions was enhanced upon hypox-ia for most of the cell lines, even in cell lines showing reduced single-cell motility. These chang-es aligned with alterations in EMT markers. While the exact mechanism underlying the differen-tial effects of hypoxia on single-cell motility and wound closure remains to be fully elucidated, we suspect that distinct patterns of cell-cell and cell-ECM contacts play a crucial role, possibly by modulating the complete or partial transition from epithelial to mesenchymal phenotype. Our study provides valuable insights into hypoxia- and HIF-related responses in various lung adeno-carcinoma models, in terms of motility, proliferation, and apoptotic activity. The high variance in cellular responses to hypoxia presents a significant challenge in cancer treatment, possibly con-tributing to the clinical failure of HIF inhibitors. Further investigations are necessary to gain a more comprehensive understanding of how hypoxia influences cancer progression across dif-ferent tumor types and microenvironmental factors. Next, in an attempt to model therapeutic resistance, we established a PDTX model of melanoma that developed resistance to vemuraf-enib, closely mimicking the acquired resistance observed in clinical settings. This model pro-vides a valuable platform for investigating the mechanisms underlying BRAF inhibitor re-sistance in melanoma. Through comprehensive transcriptomic analysis, we identified potential resistance markers, including CD27 and IFI27, which showed distinct expression patterns across treatment stages. However, we failed to validate them on the protein level. Notably, our resistant tumors did not exhibit commonly reported resistance mechanisms, such as BRAF/CRAF activation or enhanced AKT-mTOR signaling possibly mirroring RAF/MEK/ERK pathway-independent resistance mechanisms.
