Pancreatic Cancer Translational Research Group, Prince of Wales Clinical School and School of Medical Sciences, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales Sydney, New South Wales, Australia.
Cancer Res. 2021 Jul 1;81(13):3461-3479. doi: 10.1158/0008-5472.CAN-20-2496. Epub 2021 May 12.
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. SIGNIFICANCE: 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.
癌症相关成纤维细胞（CAF）通过促进肿瘤的信号和纤维化的产生来促进胰腺导管腺癌（PDAC）的进展，后者为药物的产生创造了物理屏障。因此，CAF 抑制是 PDAC 任何治疗方法的理想组成部分。SLC7A11 是一种胱氨酸转运蛋白，已被确定为 PDAC 细胞中的一个潜在治疗靶点。然而，以前的研究尚未评估 SLC7A11 在 PDAC 肿瘤基质中的作用及其预后意义。在这里，我们表明 SLC7A11 在人 PDAC 肿瘤基质中的高表达，而不是肿瘤细胞中的表达，与总体生存率较差独立相关。正交方法表明，PDAC 衍生的 CAF 高度依赖 SLC7A11 摄取胱氨酸和合成谷胱甘肽，而 SLC7A11 抑制显著降低 CAF 的增殖，降低其对氧化应激的抵抗力，并抑制其重塑胶原蛋白和支持 PDAC 细胞生长的能力。重要的是，特异性敲除转 PDAC 肿瘤中的 SLC7A11 肿瘤部位并不影响肿瘤生长，这表明基质可以在很大程度上影响 PDAC 肿瘤对 SLC7A11 抑制的反应。在利用人 PDAC 细胞和 CAF 的小鼠原位 PDAC 模型中，需要在两种细胞类型中稳定敲低 SLC7A11 以减少肿瘤生长、转移扩散和肿瘤内纤维化，这表明靶向 SLC7A11 在两个部位都很重要。最后，我们实验室开发的针对 SLC7A11 的纳米颗粒基因沉默药物治疗可减少原位 PDAC 肿瘤中的肿瘤生长、转移、CAF 激活和纤维化。总的来说，这些发现确定了 SLC7A11 在支持肿瘤生长的 PDAC 衍生 CAF 中的重要作用。意义：本研究表明，PDAC 基质细胞中的 SLC7A11 对于 CAF 的促肿瘤活性很重要，并验证了一种临床转化的纳米药物，用于治疗 PDAC 中的 SLC7A11 抑制。
