| First Author | Sharbeen G | Year | 2021 |
| Journal | Cancer Res | Volume | 81 |
| Issue | 13 | Pages | 3461-3479 |
| PubMed ID | 33980655 | Mgi Jnum | J:307151 |
| Mgi Id | MGI:6719148 | Doi | 10.1158/0008-5472.CAN-20-2496 |
| Citation | Sharbeen G, et al. (2021) Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition. Cancer Res |
| abstractText | Cancer-Associated Fibroblasts (CAF) are major contributors to pancreatic ductal adenocarcinoma (PDAC) progression through pro-tumor signaling and the generation of fibrosis that creates a physical barrier to drugs. CAF inhibition is thus an ideal component of any therapeutic approach for PDAC. SLC7A11, a cystine transporter, has been identified as a potential therapeutic target in PDAC cells. However, the role of SLC7A11 in PDAC tumor stroma and its prognostic significance has not been evaluated. Here we show that high expression of SLC7A11 in human PDAC tumor stroma, but not tumor cells, is independently prognostic of poor overall survival. Orthogonal approaches showed that PDAC-derived CAFs were dependent on SLC7A11 for cystine uptake and glutathione synthesis. SLC7A11 inhibition significantly decreased CAF proliferation, reduced their resistance to oxidative stress, and inhibited their ability to remodel collagen and support PDAC cell growth. Specific ablation of SLC7A11 from the tumor compartment of transgenic mice did not affect PDAC growth, suggesting the stroma can substantially influence PDAC response to SLC7A11 inhibition. In an orthotopic PDAC mouse 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 SLC7A11-silencing drug developed by our laboratory reduced PDAC tumor growth, metastasis, 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. |
