Deciphering the role of immunoglobulin secreting malignant lineages in the invasive frontiers of small cell lung cancer by scRNA-seq and spatial transcriptomics analysis
Fei Wu, Xiao Zhang, Minglei Wang, Jingxin Zhang, Minxin Chen, Ziyuan Ren, Meng Wu, Pingping Song, Jinming Yu, Dawei Chen
Abstract
Lung cancer remains the leading cause of cancer-related death worldwide 1 . Small cell lung cancer (SCLC) comprises ~14% of lung cancer and causes 200,000 deaths globally 2 . SCLC is characterized by the development of treatment resistance and the early-onset of widespread metastasis. Despite numerous clinical trials conducted over the past decades, the prognosis for SCLC patients has not significantly improved, except for the recent success of IMpower133 and CASPIAN trials employing immunotherapy strategies 3 , 4 . However, the specific mechanism of metastasis in SCLC and its tumor immune microenvironment remain largely unknown. The current classification of SCLC into molecular subsets based on the expression of four transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) has not effectively predicted prognosis or treatment response 5 . The ASCL1-high SCLC is the most common subtype of SCLC 5 . Hence, we hypothesize that the current subtyping of SCLC has significant intratumor heterogeneity. Single-cell RNA sequencing (scRNA-seq) is a powerful tool for cancer research to understand intratumor heterogeneity and tumor immune microenvironment 6 . However, the lack of spatial information limits the interpretation of cellular heterogeneity and cell–cell interactions. Here, spatial-resolved transcriptomics and multi-regional scRNA-seq were used to investigate the diversity of cancer cells in ASCL1-high SCLC collectively.