Single-cell RNA sequencing reveals distinct molecular features of high-grade lung adenocarcinoma subtypes

Abstract

Background and Aims: Studies have shown that the histopathological classification of lung adenocarcinoma (LUAD) provides prognostic information. Solid (S) and micropapillary (MP) subtypes, as a predominant subtype or even as a minor subtype, have been consistently associated with earlier recurrence and worse survival and are therefore categorized as high-grade histologic types. Deeper understanding of the molecular mechanisms underpinning the aggressive behaviors of these morphologically defined LUAD subtypes is critical to improve outcomes of LUAD patients. However, the molecular characterization of LUAD subtypes is challenging because most LUAD tumors are heterogeneous mixtures of different subtypes.

Methods: We performed single-cell RNA sequencing (scRNA-seq) of 117,266 cells collected from 18 surgically resected LUADs.

Results: Comprehensive scRNA-seq profiling of tumor microenvironment highlighted the immunosuppressive nature of S subtypes, while suggesting a therapeutic benefit with immune checkpoint inhibitors in this subset of LUAD. The analysis of cancer cells revealed that a considerable proportion of cancer cells of S subtype exhibited undifferentiated transcriptional patterns associated with poor prognosis. The analysis of cancer cells also suggested potential MP-specific marker genes expression.

Conclusion: Using single-cell transcriptomic profiling of LUAD, our study may help to understand the molecular mechanisms of aggressive phenotypes associated with high-grade subtypes of LUAD and to develop more precise, subtype-based therapeutic strategies in LUAD.