Thymidylate synthase maintains the de-differentiated state of triple negative breast cancers

Aarif Siddiqui, Paradesi Naidu Gollavilli, Annemarie Schwab, Maria Eleni Vazakidou, Pelin G Ersan, Mallika Ramakrishnan, Dick Pluim, Si'Ana Coggins, Ozge Saatci, Laura Annaratone, Jan Hm Schellens, Baek Kim, Irfan Ahmed Asangani, Suhail Ahmed Kabeer Rasheed, Caterina Marchiò, Ozgur Sahin, Paolo Ceppi

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)2223-2236
Number of pages14
JournalCell Death and Differentiation
Volume26
Issue number11
DOIs
Publication statusPublished - Nov 2019

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