Abstract 530P
Background
Current comprehension of micropapillary lung adenocarcinoma (MP-LUAD) remains circumscribed to the realms of biological behaviors and genomic landscapes. Previous studies from our institute have shown that there exist subtle and unactionable genomic alterations between MP and non-MP early-stage lung adenocarcinoma (LUAD). Therefore, deciphering the unknown non-genomic regulatory network of MP-pattern malignancy may offer opportunities to uncover more tractable therapeutic targets for MP-LUAD patients.
Methods
A retrospective cohort of 66 surgical specimens from early-stage LUAD, including MP and other histologic subtypes, was mapped as discovery and validation cohorts. High-throughput screening was performed on cryosectioned and microscopically laser capture microdissected paired micropapillary and Acinar LUAD tissue. In vitro and in vivo experiments for validation were performed using co-culture of tumor associated macrophages (TAM) and tumor cells, xenograft mice and zebrafish models. ChIP-seq, CUT&Tag-seq and RNase I-PCR were employed to profile aberrant histone modifications, transcription factor occupying and chromatin accessibility in MP-LUAD.
Results
Bulk RNA-seq after microdissection showed aberrant activation of the MYC pathway in MP. MYC overexpression fostered MP-pattern malignancy of tumor tissue in immunocompetent mice, but not in vitro. Through screening via single-cell RNA-seq, retrospective cohort, and TCGA dataset, we found aberrant accumulation of TAMs around MP tissues. in vitro co-culture and in vivo dependency experiments demonstrated that MYC overexpression in tumor cells exhibited a MP-pattern malignancy in collaboration with TAMs. Follow-up experiments revealed that, MYC interacted with the pioneer transcription factor FOSL2 induced by TGFβ secreted from TAMs, aberrantly accessible chromatin, and induced epigenetic reprogramming of MP-pattern gene transcription.
Conclusions
Our study uncovered copy number amplification-induced activation of MYC in MP-LUAD, which by recruiting TAMs, cooperatively transcriptionally regulates MP pattern genes and promotes a metastatic malignancy.
Clinical trial identification
Editorial acknowledgement
We gratefully acknowledge all members of the Jiangsu Cancer Hospital Biobank and Department of Pathology for collection and storage of surgical samples used in this study. We gratefully acknowledge Ms. Luyuan Pan and Ms. Linglu Li from the China Zebrafish Resource Center for providing wild-type AB-line zebrafish and assistance with zebrafish-based experiments. We gratefully acknowledge instructions and guidance on DNase I-PCR experiments from Lu Wang Lab, Northwest University. We gratefully acknowledge plasmids from Wafik El-Deiry Lab and Andrea Califano Lab.
Legal entity responsible for the study
Nanjing Medical University Affiliated Cancer Hospital.
Funding
National Natural Science Foundation of China.
Disclosure
All authors have declared no conflicts of interest.
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