PT  - JOURNAL ARTICLE
AU  - Konstantin Drexler
AU  - Katharina M Schmidt
AU  - Katrin Jordan
AU  - Marianne Federlin
AU  - Vladimir M Milenkovic
AU  - Gerhard Liebisch
AU  - Anna Artati
AU  - Christian Schmidl
AU  - Gregor Madej
AU  - Janina Tokarz
AU  - Alexander Cecil
AU  - Wolfgang Jagla
AU  - Silke Haerteis
AU  - Thiha Aung
AU  - Christine Wagner
AU  - Maria Kolodziejczyk
AU  - Stefanie Heinke
AU  - Evan H Stanton
AU  - Barbara Schwertner
AU  - Dania Riegel
AU  - Christian H Wetzel
AU  - Wolfgang Buchalla
AU  - Martin Proescholdt
AU  - Christoph A Klein
AU  - Mark Berneburg
AU  - Hans J Schlitt
AU  - Thomas Brabletz
AU  - Christine Ziegler
AU  - Eric K Parkinson
AU  - Andreas Gaumann
AU  - Edward K Geissler
AU  - Jerzy Adamski
AU  - Sebastian Haferkamp
AU  - Maria E Mycielska
TI  - Cancer-associated cells release citrate to support tumour metastatic progression
AID  - 10.26508/lsa.202000903
DP  - 2021 Jun 01
TA  - Life Science Alliance
PG  - e202000903
VI  - 4
IP  - 6
4099  - https://www.life-science-alliance.org/content/4/6/e202000903.short
4100  - https://www.life-science-alliance.org/content/4/6/e202000903.full
SO  - Life Sci. Alliance2021 Jun 01; 4
AB  - Citrate is important for lipid synthesis and epigenetic regulation in addition to ATP production. We have previously reported that cancer cells import extracellular citrate via the pmCiC transporter to support their metabolism. Here, we show for the first time that citrate is supplied to cancer by cancer-associated stroma (CAS) and also that citrate synthesis and release is one of the latter’s major metabolic tasks. Citrate release from CAS is controlled by cancer cells through cross-cellular communication. The availability of citrate from CAS regulated the cytokine profile, metabolism and features of cellular invasion. Moreover, citrate released by CAS is involved in inducing cancer progression especially enhancing invasiveness and organ colonisation. In line with the in vitro observations, we show that depriving cancer cells of citrate using gluconate, a specific inhibitor of pmCiC, significantly reduced the growth and metastatic spread of human pancreatic cancer cells in vivo and muted stromal activation and angiogenesis. We conclude that citrate is supplied to tumour cells by CAS and citrate uptake plays a significant role in cancer metastatic progression.