Hypoxic activation of PFKFB4 in breast tumor microenvironment shapes metabolic and cellular plasticity to accentuate metastatic competence

• Published in: Cell reports (Cambridge) 2022-12, Vol.41 (10), p.111756-111756, Article 111756
• Main Authors: Dai, Tao, Rosario, Spencer R., Katsuta, Eriko, Sawant Dessai, Abhisha, Paterson, Emily J., Novickis, Aaron T., Cortes Gomez, Eduardo, Zhu, Bokai, Liu, Song, Wang, Hai, Abrams, Scott I., Seshadri, Mukund, Bshara, Wiam, Dasgupta, Subhamoy
• Format: Article
• Language: English
• Subjects: Animals; breast cancer; Cell Plasticity; hypoxia; metabolism; Metabolomics; metastasis; Mice; redox; stress; transcription; Tumor Microenvironment
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111756

Cancer cells encounter a hostile tumor microenvironment (TME), and their adaptations to metabolic stresses determine metastatic competence. Here, we show that the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) is induced in hypoxic tumors acquiring metabolic plasticity and invasive phenotype. In mouse models of breast cancer, genetic ablation of PFKFB4 significantly delays distant organ metastasis, reducing local lymph node invasion by suppressing expression of invasive gene signature including integrin β3. Photoacoustic imaging followed by metabolomics analyses of hypoxic tumors show that PFKFB4 drives metabolic flexibility, enabling rapid detoxification of reactive oxygen species favoring survival under selective pressure. Mechanistically, hypoxic induction triggers nuclear translocation of PFKFB4 accentuating non-canonical transcriptional activation of HIF-1α, and breast cancer patients with increased nuclear PFKFB4 in their tumors are found to be significantly associated with poor prognosis. Our findings imply that PFKFB4 induction is crucial for tumor cell adaptation in the hypoxic TME that determines metastatic competence. [Display omitted] •Hypoxic TNBC microenvironment induces metabolic enzyme PFKFB4•PFKFB4 activates invasive phenotype by transcriptional activation of integrin β3•Activation of PFKFB4 promotes metabolic rewiring by increasing glutathione levels•Hypoxia localizes PFKFB4 to the nucleus, creating genetic and metabolic plasticity Dai et al. show a novel mechanism by which metabolic stresses in the primary tumors accentuate metastatic potential. The metabolic enzyme PFKFB4, induced in hypoxic breast tumors, promotes integrin-dependent metastatic potential and rewiring of cellular metabolism. Increased PFKFB4 expression prognosticates TNBC patients with poor outcome.