Abstract LB054: Prometastatic effect of ATX derived from alveolar type II pneumocytes and B16F10 melanoma cells

Abstract

Abstract Although metastasis is the principal cause of cancer-related deaths, the molecular aspects of the role of stromal cells in the establishment of the metastatic niche remain poorly understood. One of the most prevalent sites for cancer metastasis is the lungs. According to recent research, lung stromal cells such as bronchial epithelial cells and resident macrophages secrete autotaxin (ATX), an enzyme with lysophospholipase D activity that promotes cancer progression. In fact, several studies have shown that many cell types in the lung stroma could potentially provide a rich source of ATX in diseases. In the present study, we sought to determine whether ATX derived from alveolar type II epithelial (ATII) pneumocytes could modulate the progression of lung metastasis, which has not been evaluated previously. To accomplish this, we used the B16-F10 syngeneic melanoma model, which readily metastasize to the lungs when injected intravenously. Because B16-F10 cells express high levels of ATX, we used the CRISPR-Cas9 technology to knockout (KO) ATX in B16-F10 cells, eliminating the contribution of tumor-derived ATX in lung metastasis. Next, we used the inducible Cre/lox system (Sftpc-CreERT2/Enpp2fl/fl) to generate conditional KO mice in which ATX is specifically deleted in ATII cells (i.e. Sftpc-KO). Injection of ATX-KO B16-F10 cells into Sftpc-KO or Sftpc-WT control littermates allows us to investigate the specific contribution of ATII-derived ATX in lung metastasis. We found that targeted KO of ATX in ATII cells significantly reduced the metastatic burden of ATX-KO B16-F10 cells by 30% compared to Sftpc-WT mice (unpaired t-test, p=0.0283), suggesting that ATX derived from ATII cells could affect the metastatic progression. We detected upregulated levels of cytokines such as IFNγ (unpaired t-test, p<0.0001) and TNFα (unpaired t-test, p=0.0003), which could favor the increase in infiltrating CD8+-T cells observed in the tumor regions of Sftpc-KO mice. Taken together, our results highlight the contribution of host ATII cells as a stromal source of ATX in the progression of melanoma lung metastasis. Citation Format: Melanie A. Dacheux, Sue Chin Lee, Yoojin Shin, Derek D. Norman, Kuan-Hung Lin, Gabor J. Tigyi. Prometastatic effect of ATX derived from alveolar type II pneumocytes and B16F10 melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB054.