A team of Galician researchers reveals that the POU1F1 protein is capable of modifying the phenotype of cancer cells.

Deepen the knowledge of the metabolic reprogramming of tumor cells is the basis of the new discovery of the Center for Research in Molecular Medicine and Chronic Diseases (CiMUS) of the University of Santiago de Compostela.

The group led by Román Pérez-Fernández, has just revealed that the POU1F1 protein, through the regulation of LDHA, it is capable of modifying the phenotype of cancer cells and favoring tumor progression and metastasis.

The finding, which opens the door to New and promising therapeutic strategies in cancer, has just been published in the prestigious magazine Oncogene, of the Springer-Nature publishing group.

Metabolic reprogramming is considered a hallmark of cancer. The callWarburg effect on tumor cells It has been known for almost a century, but the specific factors that regulate it (lactate generation) and its effects on cells and the tumor microenvironment are still not well understood.

In this work, using breast cancer cell lines, human primary breast tumor cultures and immunodeficient mouse models, the team coordinated by Román Pérez from CiMUS demonstrated that the transcription factor POU1F1 is functionally and clinically related to metabolic reprogramming in breast cancer cells and with the activation of fibroblasts, the most common type of cells in the tumor mass.

“Lactate increases the proliferation, migration and invasion of breast cancer cells. In addition, it activates normal fibroblasts transforming them into cancer-associated fibroblasts. Clinically, in breast cancer patients, increased expression of POU1F1 and LDHA is related to the formation of metastases. Our data indicate that POU1F1 induces metabolic reprogramming through the regulation of LDHA in human breast tumor cells, modifying both the phenotype / characteristics of cancer cells and fibroblasts, and promoting tumor progression ”, explains the first author of the article Anxo Martínez-Ordóñez.

The role of the protein or transcription factor POU1F1 in the development of the pituitary gland and its homeostasis is well known. However, it is alsogood it is expressed in tissues such as the human breast. The group led by Pérez-Fernández has been studying the role of POU1F1 in breast cancer for several years, assuming that high levels of POU1F1 induce tumor promotion and metastasis. At the beginning of the investigation, they observed that POU1F1 induced a clear enrichment in the glycolysis pathway.

Additional bioinformatic analysis would not only confirm that breast cancer relies on increased glycolytic activity to progress, but also shows a positive correlation between POU1F1 and Lactate dehydrogenase A (LDHA), the key enzyme that generates lactate. These interesting preliminary data suggested a link between aerobic glycolysis and POU1F1 through the regulation of LDHA ”, clarifies Martinez-Ordóñez.

To test the hypothesis that POU1F1 could regulate the LDHA gene at the transcriptional level, they began to generate breast cancer cell lines with overexpression of POU1F1 and elimination of LDHA.

They then evaluated the key in vitro characteristics of cancer progression. Once they obtained results in line with their hypothesis, they switched to in vivo models, for which they used immunodeficient mice. “As we expected, says Román Pérez, POU1F1 greatly increased tumor volume compared to controls. In collaboration with Dr. Pablo Aguiar from the Molecular Imaging group at IDIS, and using PET / CTC images, frequently used in clinical practice with patients, a greater uptake of marked glucose was demonstrated in these tumors, which decreases significantly when LDHA is eliminated.

In addition, the analysis of breast cancer patient data showed that the expression of POU1F1 / LDHA was associated with a worse prognosis ”. To finalize the project and given that there was more and more evidence connecting metabolic reprogramming with the modulation of the tumor microenvironment, they studied whether POU1F1 could have an impact on fibroblasts. They demonstrated that normal fibroblasts were transformed towards a tumor phenotype, thus collaborating with the tumor cells themselves, inducing greater tumor progression.