RT Journal Article
SR Electronic
T1 Heterogeneity in PHGDH protein expression potentiates cancer cell dissemination and metastasis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.24.427949
DO 10.1101/2021.01.24.427949
A1 Matteo Rossi
A1 Ginevra Doglioni
A1 Laura Bornes
A1 Dorien Broekaert
A1 Mélanie Planque
A1 Juan Fernández-García
A1 Gianmarco Rinaldi
A1 Joke Van Elsen
A1 David Nittner
A1 Cristina Jauset
A1 Francesca Rizzollo
A1 Carla Riera Domingo
A1 Martin F Orth
A1 Lacey E Dobrolecki
A1 Thomas Van Brussel
A1 Shao Thing Teoh
A1 Arin B Aurora
A1 Guy Eelen
A1 Panagiotis Karras
A1 Karl Sotlar
A1 Harald Bartsch
A1 Jean-Christophe Marine
A1 Peter Carmeliet
A1 Sean J Morrison
A1 Michael T Lewis
A1 Gregory J Hannon
A1 Massimiliano Mazzone
A1 Diether Lambrechts
A1 Jacco van Rheenen
A1 Thomas G P Grünewald
A1 Sophia Y Lunt
A1 Sarah-Maria Fendt
YR 2021
UL http://biorxiv.org/content/early/2021/01/26/2021.01.24.427949.abstract
AB Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs. Genetic, transcriptional and translational intra-tumor heterogeneity contributes to this dynamic process. Beyond this, metabolic intra-tumor heterogeneity has also been observed, yet its role for cancer progression remains largely elusive. Here, we discovered that intra-tumor heterogeneity in phosphoglycerate dehydrogenase (PHGDH) protein expression drives breast cancer cell dissemination and metastasis formation. Specifically, we observed intra-tumor heterogeneous PHGDH expression in primary breast tumors, with low PHGDH expression being indicative of metastasis in patients. In mice, Phgdh protein, but not mRNA, expression is low in circulating tumor cells and early metastatic lesions, leading to increased dissemination and metastasis formation. Mechanistically, low PHGDH protein expression induces an imbalance in glycolysis that can activate sialic acid synthesis. Consequently, cancer cells undergo a partial EMT and show increased p38 as well as SRC phosphorylation, which activate cellular programs of dissemination. In turn, inhibition of sialic acid synthesis through knock-out of cytidine monophosphate N-acetylneuraminic acid synthetase (CMAS) counteracts the increased cancer cell dissemination and metastasis induced by low PHGDH expression. In conclusion, we find that heterogeneity in PHGDH protein expression promotes cancer cell dissemination and metastasis formation.Competing Interest StatementS-MF has received funding from Bayer AG, Merck and Black Belt Therapeutics and has consulted for Fund +. All other authors declare no competing interests.