Cancer-associated cells release citrate to support tumour metastatic progression.

Konstantin Drexler ,Hans J Schlitt ,Vladimir M Milenkovic ,Eric K Parkinson ,Janina Tokarz ,Evan H Stanton ,Marianne Federlin ,Tin Aung ,B Schwertner ,Edward K Geissler ,Christoph Klein ,Katharina Schmidt ,Thomas Brabletz ,Christine Ziegler ,Christian H Wetzel ,Jerzy Adamski ,Alexander Cecil ,Andreas Gäumann ,Wolfgang Buchalla ,Maria Kolodziejczyk ,Dania Riegel ,Mark Berneburg ,Martin Proescholdt ,Silke Haerteis ,Gerhard Liebisch ,Wolfgang Jagla ,M Gregor Madej ,Katrin Jordan ,Sebastian Haferkamp ,Christian Schmidl ,Christine Wagner ,Anna Artati ,Stefanie Heinke ,Maria E Mycielska

doi:10.26508/lsa.202000903

Abstract

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.

Highlights

Citrate is a central metabolite used by cancer cells for fatty acid synthesis (Wang et al, 2016)
The levels of pyruvate which can be used by cells for intracellular citrate synthesis remained the same in the conditioned media from cancer cells and fibroblasts, suggesting that pyruvate does not play a significant role in Cancer-associated fibroblasts (CAFs)’s support of cancer metabolism
Our data show that the metabolic activity of CAFs depends on extracellular citrate availability to cancer cells; it is regulated in the cancer environment

Summary

Introduction

Citrate is a central metabolite used by cancer cells for fatty acid synthesis (Wang et al, 2016). We have recently discovered that cancer cells can import extracellular citrate by using a plasma membrane citrate transporter (pmCiC; Mycielska et al, 2018). This transporter has been cloned from the citrate releasing prostate secretory epithelial cells (Mazurek et al, 2010) and determined to change citrate transport direction, depending on the cell type in which it is expressed (Mazurek et al, 2010; Mycielska et al, 2018). Application of a specific pmCiC inhibitor, gluconate, slowed xenograft growth in vivo by incompletely understood mechanisms (Mycielska et al, 2018, 2019)

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