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-CreERT2/Enpp2fl/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 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.
