American Association for Cancer Research
00085472can202496-sup-248020_3_supp_7068460_qry9qb.pdf (232.64 kB)

Figure S2 from Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Determine Response to SLC7A11 Inhibition

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journal contribution
posted on 2023-03-31, 04:21 authored by George Sharbeen, Joshua A. McCarroll, Anouschka Akerman, Chantal Kopecky, Janet Youkhana, John Kokkinos, Jeff Holst, Cyrille Boyer, Mert Erkan, David Goldstein, Paul Timpson, Thomas R. Cox, Brooke A. Pereira, Jessica L. Chitty, Sigrid K. Fey, Arafath K. Najumudeen, Andrew D. Campbell, Owen J. Sansom, Rosa Mistica C. Ignacio, Stephanie Naim, Jie Liu, Nelson Russia, Julia Lee, Angela Chou, Amber Johns, Anthony J. Gill, Estrella Gonzales-Aloy, Val Gebski, Yi Fang Guan, Marina Pajic, Nigel Turner, Minoti V. Apte, Thomas P. Davis, Jennifer P. Morton, Koroush S. Haghighi, Jorjina Kasparian, Benjamin J. McLean, Yordanos F. Setargew, Phoebe A. Phillips

Anti-proliferative effect of SLC7A11 knockdown in CAFs and the effect of SLC7A11 inhibition in MiaPaCa-2 PDAC cells and normal human pancreatic ductal epithelial (HPDE) cells.


NHMRC project grant

Avner Grant from PanKind

The Australian Pancreatic Cancer Foundation


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 Senior Research Fellowship

Len Ainsworth Pancreatic Cancer Fellowship and support from Suttons

Cancer Council NSW



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.