RT Journal Article
SR Electronic
T1 Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.07.12.199638
DO 10.1101/2020.07.12.199638
A1 George Sharbeen
A1 Joshua A. McCarroll
A1 Anouschka Akerman
A1 Chantal Kopecky
A1 Janet Youkhana
A1 Jeff Holst
A1 Cyrille Boyer
A1 Mert Erkan
A1 David Goldstein
A1 Paul Timpson
A1 Thomas R. Cox
A1 Brooke A. Pereira
A1 Jessica L. Chitty
A1 Sigrid Fey
A1 Arafath K. Najumudeen
A1 Andrew D. Campbell
A1 Owen J. Sansom
A1 Rosa Mistica C. Ignacio
A1 Stephanie Naim
A1 Jie Liu
A1 Nelson Russia
A1 Julia Lee
A1 Angela Chou
A1 Amber Johns
A1 Anthony Gill
A1 Estrella Gonzales-Aloy
A1 John Kokkinos
A1 Val Gebski
A1 Nigel Turner
A1 Minoti Apte
A1 Thomas P. Davis
A1 Jennifer P. Morton
A1 Koroush Haghighi
A1 Australian Pancreatic Cancer Genome Initiative
A1 Phoebe A. Phillips
YR 2020
UL http://biorxiv.org/content/early/2020/07/12/2020.07.12.199638.abstract
AB Cancer-Associated Fibroblasts (CAFs) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression, through pro-tumour cross-talk and the generation of fibrosis (physical barrier to drugs). CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11 is a cystine transporter that has been identified as a potential therapeutic target in PDAC cells. However, no prior study has evaluated the role of SLC7A11 in PDAC tumour stroma and its prognostic significance. Herein we show that high expression of SLC7A11 in PDAC tumour stroma (but not tumour cells) is independently prognostic of poorer overall survival. We demonstrate using orthogonal approaches that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis, and that SLC7A11 inhibition significantly decreases their proliferation, reduces their resistance to oxidative stress and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, our paradigm-shifting work demonstrates the need to inhibit SLC7A11 in the PDAC stroma, as genetic ablation of SLC7A11 in PDAC cells alone is not enough to reduce tumour growth. Finally, our work validates that a nano-based gene-silencing drug against SLC7A11, developed by our group, reduces PDAC tumour growth, CAF activation and fibrosis in a mouse model of PDAC.Competing Interest StatementThe authors have declared no competing interest.