2. Academic Validation
  3. Excessive MYC Orchestrates Macrophages induced Chromatin Remodeling to Sustain Micropapillary-Patterned Malignancy in Lung Adenocarcinoma

Excessive MYC Orchestrates Macrophages induced Chromatin Remodeling to Sustain Micropapillary-Patterned Malignancy in Lung Adenocarcinoma

  • Adv Sci (Weinh). 2025 Feb 3:e2403851. doi: 10.1002/advs.202403851.
Xuming Song 1 2 3,  Zehao Pan 1 2 3,  Yi Zhang 2 4,  Wenmin Yang 1 2 5,  Te Zhang 1 2 6,  Hui Wang 1 2 3,  Yuzhong Chen 1 2 3,  Xinnian Yu 1 2 3,  Hanlin Ding 1 2 3,  Rutao Li 2 7,  Pengfei Ge 1 2 3,  Lin Xu 1 2 8,  Gaochao Dong 1 2,  Feng Jiang 1 2
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, 210009, P. R. China.
  • 2 Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing, 210000, P. R. China.
  • 3 The Fourth Clinical College of Nanjing Medical University, Nanjing, 210000, P. R. China.
  • 4 Department of Pathology, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, 210009, P. R. China.
  • 5 Department of Pathology, Nanjing Drum Tower hospital, Nanjing, 210008, P.R. China.
  • 6 Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60201, USA.
  • 7 Department of Thoracic Surgery, The Fourth Affiliated Hospital of Soochow University, Nanjing, 215000, P. R. China.
  • 8 Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211116, P. R. China.
PMID: 39899538 DOI: 10.1002/advs.202403851
Abstract

Current understanding of micropapillary (MP)-subtype lung adenocarcinoma (LUAD) remains confined to biological activities and genomic landscapes. Unraveling the major regulatory programs underlying MP patterned malignancy offers opportunities to identify more feasible therapeutic targets for patients with MP LUAD. This study shows that patients with MP subtype LUAD have aberrant activation of the MYC pathway compared to patients with Other subtypes. In vitro and xenograft mouse model studies reveal that MP pattern in malignancy cannot be solely due to aberrant MYC expression but requires the involvement of M2-like macrophages. Excessively expressed MYC leads to the accumulation of M2-like macrophages from the bone marrow, which secretes TGFβ, to induce the expression of FOSL2 in tumor cells, thereby remodeling chromatin accessibility at promoter regions of MP-pattern genes to promote the MYC-mediated de novo transcriptional regulation of these genes. Additionally, the MP-pattern in malignancy can be effectively alleviated by disrupting the TGFβ-FOSL2 axis. These findings reveal new functions for the M2-like macrophage-TGFβ-FOSL2 axis in MYC-overexpressing MP-subtype LUAD, identifying targetable vulnerabilities in this pathway.

Keywords

M2‐like macrophages; MYC; chromatin accessibility; micropapillary lung adenocarcinoma.

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