PT  - JOURNAL ARTICLE
AU  - Marzia Scortegagna
AU  - Yuanning Du
AU  - Linda M. Bradley
AU  - Kun Wang
AU  - Eytan Ruppin
AU  - Rabi Murad
AU  - Ze’ev A. Ronai
TI  - Control of alveolar macrophage differentiation by Siah1a/2 ubiquitin ligases limits carcinogen-induced lung adenocarcinoma
AID  - 10.1101/2022.09.14.508032
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.09.14.508032
4099  - http://biorxiv.org/content/early/2022/09/17/2022.09.14.508032.short
4100  - http://biorxiv.org/content/early/2022/09/17/2022.09.14.508032.full
AB  - Tumor microenvironment components, including T and myeloid cells, play important roles in lung adenocarcinoma (LADC) progression and response to therapy. Here, we identify a role for Siah1a/2 ubiquitin ligases in controlling alveolar macrophage (AM) differentiation and urethane-induced LADC. Genetic ablation of Siah1a/2 in AMs enriched their immature state, coinciding with increased pro-tumorigenic and inflammatory gene signatures and abundance of Siah1a/2 substrates NRF2 and β-catenin. Urethane administration to mice enriched the population of monocytic and immature-like AMs, which were more prevalent in the lungs of mice carrying Siah1a/2-ablated macrophages. While resembling transitional profibrotic macrophages often seen in lung fibrosis, enrichment of immature AMs coincided with the development of more frequent and larger lung tumors in urethane-treated mice harboring Siah1a/2 ablated macrophages compared with controls. Gene expression signature of Siah1a/2 ablated immature-like AMs is associated with increased infiltration of CD14+ immune cells and worse survival of LADC patients. Our findings identify Siah1a/2 as gatekeepers of cancer development by controlling AM differentiation and profibrotic phenotypes contributing to carcinogen-induced lung cancer.Competing Interest StatementZAR is co-founder and scientific advisor of Pangea BioMed