Abstract
Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell transcriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions.
Highlights
Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer
To elucidate the cellular dynamics in Lung adenocarcinoma (LUAD) progression, tumor from primary lung tissues, pleural fluids, and lymph node or brain metastases were obtained from 44 patients with treatment-naïve LUAD during endobronchial ultrasound/bronchoscopy biopsy or surgical resection (Fig. 1a, Supplementary Data 1)
We cataloged 208,506 cells into nine distinct cell lineages annotated with canonical marker gene expression (Fig. 1b-d, Supplementary Fig. 1, Supplementary Data 2), identifying epithelial, stromal, and immune cells (T, natural killer (NK), B, myeloid, and MAST cells) as the common cell types, and oligodendrocytes only in brain metastases
Summary
Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. We present single-cell transcriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions. Previous scRNA-seq studies related to lung cancer have been limited to early stage primary tumors and normal tissues resected from a small number of samples of mixed histological types[9,10]. We report the comprehensive single-cell transcriptome profiling of LUAD from early to advanced stages of primary cancer and distant metastases, and unveil cellular dynamics and molecular features associated with the tumor progression
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