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

Siddiqui A, Gollavilli PN, Schwab A, Vazakidou ME, Ersan PG, Ramakrishnan M, Pluim D, Coggins SA, Saatci O, Annaratone L, HM Schellens J, Kim B, Asangani IA, Rasheed SAK, Marchiò C, Sahin O, Ceppi P (2019)

Publication Type: Journal article

Publication year: 2019

Journal

DOI: 10.1038/s41418-019-0289-6

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.

Authors with CRIS profile

Involved external institutions

Emory University United States (USA) (US) Bilkent University / Bilkent Üniversitesi Turkey (TR) University of South Carolina United States (USA) (US) Duke-NUS Medical School / 杜克—国大医学研究生院 Singapore (SG) University of Pennsylvania United States (USA) (US) Georg-Speyer-Haus Germany (DE) University of Turin / Università degli Studi di Torino (UNITO) Italy (IT) Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI / NKI-AVL) Netherlands (NL)

How to cite

APA:

Siddiqui, A., Gollavilli, P.N., Schwab, A., Vazakidou, M.E., Ersan, P.G., Ramakrishnan, M.,... Ceppi, P. (2019). Thymidylate synthase maintains the de-differentiated state of triple negative breast cancers. Cell Death and Differentiation. https://doi.org/10.1038/s41418-019-0289-6

MLA:

Siddiqui, Aarif, et al. "Thymidylate synthase maintains the de-differentiated state of triple negative breast cancers." Cell Death and Differentiation (2019).

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