| First Author | Breitenecker K | Year | 2024 |
| Journal | Int J Mol Sci | Volume | 25 |
| Issue | 8 | PubMed ID | 38673795 |
| Mgi Jnum | J:347597 | Mgi Id | MGI:7625242 |
| Doi | 10.3390/ijms25084202 | Citation | Breitenecker K, et al. (2024) Tumor-Extrinsic Axl Expression Shapes an Inflammatory Microenvironment Independent of Tumor Cell Promoting Axl Signaling in Hepatocellular Carcinoma. Int J Mol Sci 25(8) |
| abstractText | The activation of the receptor tyrosine kinase Axl by Gas6 is a major driver of tumorigenesis. Despite recent insights, tumor cell-intrinsic and -extrinsic Axl functions are poorly understood in hepatocellular carcinoma (HCC). Thus, we analyzed the cell-specific aspects of Axl in liver cancer cells and in the tumor microenvironment. We show that tumor-intrinsic Axl expression decreased the survival of mice and elevated the number of pulmonary metastases in a model of resection-based tumor recurrence. Axl expression increased the invasion of hepatospheres by the activation of Akt signaling and a partial epithelial-to-mesenchymal transition (EMT). However, the liver tumor burden of Axl(+/+) mice induced by diethylnitrosamine plus carbon tetrachloride was reduced compared to systemic Axl(-/-) mice. Tumors of Axl(+/+) mice were highly infiltrated with cytotoxic cells, suggesting a key immune-modulatory role of Axl. Interestingly, hepatocyte-specific Axl deficiency did not alter T cell infiltration, indicating that these changes are independent of tumor cell-intrinsic Axl. In this context, we observed an upregulation of multiple chemokines in Axl(+/+) compared to Axl(-/-) tumors, correlating with HCC patient data. In line with this, Axl is associated with a cytotoxic immune signature in HCC patients. Together these data show that tumor-intrinsic Axl expression fosters progression, while tumor-extrinsic Axl expression shapes an inflammatory microenvironment. |
