Prometastatic Effect of ATX Derived from Alveolar Type II Pneumocytes and B16-F10 Melanoma Cells

Simple Summary Only a few studies have reported a role of alveolar type II epithelial (ATII) pneumocytes in the development of the lung metastatic niche. In the present study, we investigated the contribution of autotaxin (ATX) produced by ATII cells in driving the progression of B16-F10 melanoma-derived lung metastases. We found that the metastatic burden is reduced when the ATX gene is deleted from both ATII and B16-F10 cells. We detected increased levels of cytokines such as IFN gamma and TNF alpha, which could favor the increase in infiltrating CD8(+) T cells observed in the tumor regions. Our findings suggest that a concomitant inhibition of ATX from both stromal and cancer cells may, in part, modulate the antitumor response to better control metastatic progression. Although metastases are 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 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 metastasizes to the lungs when injected intravenously. Because B16-F10 cells express high levels of ATX, we used the CRISPR-Cas9 technology to knock out the ATX gene in B16-F10 cells, eliminating the contribution of tumor-derived ATX in lung metastasis. Next, we used the inducible Cre/loxP system (Sftpc-CreER(T2)/Enpp2(fl/fl)) to generate conditional knockout (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 allowed 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% (unpaired t-test, p = 0.028) compared to Sftpc-WT control mice, suggesting that ATX derived from ATII cells could affect the metastatic progression. We detected upregulated levels of cytokines such as IFN gamma (unpaired t-test, p < 0.0001) and TNF alpha (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.