TY - JOUR T1 - Cancer-associated cells release citrate to support tumour metastatic progression JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202000903 VL - 4 IS - 6 SP - e202000903 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 Y1 - 2021/06/01 UR - https://www.life-science-alliance.org/content/4/6/e202000903.abstract N2 - 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. ER -