Browsing by Author "Schwab, A."
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Item Open Access Polyol pathway links glucose metabolism to the aggressiveness of cancer cells(American Association for Cancer Research, 2018) Schwab, A.; Siddiqui, A.; Vazakidou, M. E.; Napoli, F.; Bottcher, M.; Menchicchi, B.; Raza, Umar; Saatçi, Özge; Krebs, A. M.; Ferrazzi, F.; Rapa, I.; Wilde, K. D.; Waldner, M. J.; Ekici, A. B.; Rasheed, S. A. K.; Mougiakakos, D.; Oefner, P. J.; Şahin, Özgür; Volante, M.; Greten, F. R.; Brabletz, T.; Ceppi, P.Cancer cells alter their metabolism to support their malignant properties. In this study, we report that the glucose-transforming polyol pathway (PP) gene aldo-keto-reductase-1-member-B1 (AKR1B1) strongly correlates with epithelial-to-mesenchymal transition (EMT). This association was confirmed in samples from lung cancer patients and from an EMT-driven colon cancer mouse model with p53 deletion. In vitro, mesenchymal-like cancer cells showed increased AKR1B1 levels, and AKR1B1 knockdown was sufficient to revert EMT. An equivalent level of EMT suppression was measured by targeting the downstream enzyme sorbitol-dehydrogenase (SORD), further pointing at the involvement of the PP. Comparative RNA sequencing confirmed a profound alteration of EMT in PP-deficient cells, revealing a strong repression of TGFb signature genes. Excess glucose was found to promote EMT through autocrine TGFb stimulation, while PP-deficient cells were refractory to glucose-induced EMT. These data show that PP represents a molecular link between glucose metabolism, cancer differentiation, and aggressiveness, and may serve as a novel therapeutic target.Item Open Access Thymidylate synthase maintains the de-differentiated state of triple negative breast cancers(Nature Publishing Group, 2019-02) Siddiqui, A.; Gollavilli, P. N.; Schwab, A.; Vazakidou, M. E.; Ersan, Pelin G.; Ramakrishnan, M.; Pluim, D.; Coggins, Si’A.; Saatçi, Ö.; Annaratone, L.; Schellens, J. HM; Kim, B.; Asangani, İ. A.; Rasheed, S. A. K.; Marchiò, C.; Şahin, Özgür; Ceppi, P.Cancer cells frequently boost nucleotide metabolism (NM) to support their increased proliferation, but the consequences of elevated NM on tumor de-differentiation are mostly unexplored. Here, we identified a role for thymidylate synthase (TS), a NM enzyme and established drug target, in cancer cell de-differentiation and investigated its clinical significance in breast cancer (BC). In vitro, TS knockdown increased the population of CD24+ differentiated cells, and attenuated migration and sphere-formation. RNA-seq profiling indicated repression of epithelial-to-mesenchymal transition (EMT) signature genes upon TS knockdown, and TS-deficient cells showed an increased ability to invade and metastasize in vivo, consistent with the occurrence of a partial EMT phenotype. Mechanistically, TS enzymatic activity was found essential for maintenance of the EMT/stem-like state by fueling a dihydropyrimidine dehydrogenase—dependent pyrimidine catabolism. In patient tissues, TS levels were found significantly higher in poorly differentiated and in triple negative BC, and strongly correlated with worse prognosis. The present study provides the rationale to study in-depth the role of NM at the crossroads of proliferation and differentiation, and depicts new avenues for the design of novel drug combinations for the treatment of BC.