Redundant MYC orchestrates M2-like macrophages induced chromatin remodeling to sustain micropapillary-pattern malignancy in Lung Adenocarcinoma

Current comprehension of micropapillary (MP)-subtype lung adenocarcinoma (LUAD) remains circumscribed to biological behaviors and genomic landscapes. Unraveling the core regulatory programs underlying MP-pattern malignancy offers opportunities to identify more feasible therapeutic targets for patients with MP-LUAD. We show aberrant activation of the MYC pathway in MP-subtype LUAD compared with other subtypes. MP-pattern malignancy cannot be solely induced by aberrant MYC expression in vitro or xenograft mouse models but requires the assistance of M2-like macrophages to accomplish. Redundantly expressed MYC aggregates M2-like macrophages derived from the bone marrow to secrete TGFβ, inducing the expression of FOSL2 in tumor cells, thereby remodeling chromatin accessibility in MP-pattern gene promoters to assist MYC in occupying de novo transcriptional regulation. Moreover, effective alleviation of MP-pattern malignancy can be achieved by disrupting the TGFβ-FOSL2 axis. These findings elucidate functions of M2-like macrophage-TGFβ-FOSL2 axis in MYC-redundant MP-subtype LUAD, defining targetable vulnerabilities. Bulk RNA-seq was performed on microdissected RNA samples from 3 lung adenocarcinoma tissues containing micropapillary and acinar components. RNA-seq was also performed on A549 cell line samples subjected to the following manipulations: 1) transfection with pcDNA3 control plasmid, 2) transfection with MYC overexpression plasmid, 3) transfection with pcDNA3 control plasmid and co-culture with M2-like macrophages for 72 hours, 4) transfection with MYC overexpression plasmid and co-culture with M2-like macrophages for 72 hours. Anti-H3K27ac CUT&Tag-seq was performed on microdissected samples from 1 lung adenocarcinoma tissues containing micropapillary and acinar components. A549 cell line samples were subjected to the following manipulations: 1) transfection with pcDNA3 control plasmid, 2) transfection with MYC overexpression plasmid, 3) transfection with pcDNA3 control plasmid and co-culture with M2-like macrophages for 72 hours, 4) transfection with MYC overexpression plasmid and co-culture with M2-like macrophages for 72 hours. Anti-cMyc ChIP-seq was performed on microdissected DNA samples from 1 lung adenocarcinoma tissue containing a micropapillary component as well as on DNA samples from A549 cell line transfected with MYC overexpression plasmid and co-cultured with M2-like macrophages for 72 hours.