Funding
NHMRC project grant
Avner Grant from PanKind
The Australian Pancreatic Cancer Foundation
NHMRC CDF-I
Cancer-Institute NSW ECF/CDFs
Cancer Institute NSW Innovation Grant
Cancer Institute NSW ‘The Professor Rob Sutherland AO Make a Difference Award’
Cancer Australia/Cancer Council
Cancer Australia/Kids Cancer Project
Translational Cancer Research Network and Australian Postgraduate Award Scholarships
Australian Government Research Training Program Scholarship & UNSW Sydney Scientia PhD Scholarship
Cure Cancer Australia
Tour de Cure PhD Support Scholarship
Tour de Cure Established Research Grant
Tour de Cure Pioneering Research Grant
Cancer Research UK Core Funding and Grand Challenge grants
Pancreatic Cancer UK Future Leaders Academy
NHRMC project grants
NHMRC CDF-II
NHMRC Senior Research Fellowship
Len Ainsworth Pancreatic Cancer Fellowship and support from Suttons
Cancer Council NSW
ARTICLE ABSTRACT
Cancer-associated fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through protumor signaling and the generation of fibrosis, the latter of which creates a 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 tumor stroma and its prognostic significance. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poorer overall survival. Orthogonal approaches showed that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis and that SLC7A11 inhibition significantly decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to remodel collagen and support PDAC cell growth. Importantly, specific ablation of SLC7A11 from the tumor compartment of transgenic mouse PDAC tumors did not affect tumor growth, suggesting the stroma can substantially influence PDAC tumor response to SLC7A11 inhibition. In a mouse orthotopic PDAC model utilizing human PDAC cells and CAFs, stable knockdown of SLC7A11 was required in both cell types to reduce tumor growth, metastatic spread, and intratumoral fibrosis, demonstrating the importance of targeting SLC7A11 in both compartments. Finally, treatment with a nanoparticle gene-silencing drug against SLC7A11, developed by our laboratory, reduced PDAC tumor growth, incidence of metastases, CAF activation, and fibrosis in orthotopic PDAC tumors. Overall, these findings identify an important role of SLC7A11 in PDAC-derived CAFs in supporting tumor growth.
This study demonstrates that SLC7A11 in PDAC stromal cells is important for the tumor-promoting activity of CAFs and validates a clinically translatable nanomedicine for therapeutic SLC7A11 inhibition in PDAC.
