Unraveling Metastasis Drivers in Small Cell Lung Cancer via Human Pluripotent Stem Cell-Based Approach

SUMMARY Small cell lung cancer (SCLC) is among the most lethal malignancies, noted for its pronounced metastatic potential across solid tumors, yet the underlying mechanisms of its metastasis remain largely unknown. In this project, we aim to deploy innovative methods and tools to delve into the longstanding enigmas of SCLC metastasis, leveraging advances in technology to gain clearer insights into this complex issue. We recently developed a method to generate functionally viable pulmonary neuroendocrine cells (PNECs) from human pluripotent stem cells (hPSCs). These cells, as the putative cell of origin of SCLC, can be transformed oncogenically by inducing mutations in key SCLC genes—RB1, TP53, and MYC—resulting in tumor formation in mice that closely resembles clinical SCLC. These modified PNECs effectively replicate the critical stages of SCLC, from tumor initiation to metastatic spread, providing a robust model to investigate the cellular and molecular drivers behind the disease’s aggressive metastasis. Our research strategy integrates hPSC-derived SCLC models, clinical samples, patient-derived xenografts (PDX), and state-of-the-art technologies such as single-cell sequencing and ATAC-seq. By examining cell behavior in both primary tumors and metastatic sites, we propose to uncover essential insights into the metastatic cellular and molecular drivers of SCLC. The outcomes of this research are anticipated to shed light on why SCLC aggressively metastasizes and could lead to novel diagnostic and therapeutic approaches for this formidable cancer.