CBE Colloquia - Molecular and Cellular Mechanisms Underlying Lung Cancer Phenotypic Transition and Drug Resistance
Supporting the below United Nations Sustainable Development Goals:支持以下聯合國可持續發展目標：支持以下联合国可持续发展目标：
Lung cancer remains one of the most devastating malignancies worldwide. We demonstrate that LKB1 mutation drives adeno‑to‑squamous transition (AST) in lung cancer, and this phenotypic transition confers therapeutic resistance. Through integrative transcriptomic and epigenomic analyses, we identify ΔNp63 as a key driver of AST in modulating the response to targeted therapy. We further characterize an intermediate, high‑plasticity cell state defined by an AST plasticity signature and Krt6a expression. Notably, baseline expression of this AST signature and KRT6A correlates with poor therapeutic responses. Using multi‑omics integrative analysis of single‑cell transcriptomic data from mouse models and clinical specimens, we uncover a spatiotemporal regulatory mechanism: initially, oxidative stress triggers transient NF‑κB signaling, which sustains adenomatous identity and cell survival at an early stage. Subsequently, tumor cells at the late transitional stage secrete IL‑1α, which reprograms cancer‑associated fibroblasts (CAFs) into a leukocyte‑related subtype to promote squamous tumor growth. Based on these molecular and cellular mechanistic insights, we will discuss the development of therapeutic strategies to overcome AST‑mediated drug resistance.
Hongbin received his Ph.D. from the Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences in 2000. He conducted postdoctoral training at Beth Israel Deaconess Medical Center (2000–2004) and Dana-Farber Cancer Institute (2004–2007).
His research group focuses on deciphering the molecular mechanisms underlying lung cancer initiation, phenotypic transition, and metastasis, as well as developing novel therapeutic strategies to overcome drug resistance. His seminal contributions to lung cancer research include: 1) Identified RET fusions as oncogenic drivers in lung adenocarcinoma. 2) Established mouse models for studying lung adeno‑to‑squamous transition (AST), and demonstrated the critical role of AST in promoting resistance to molecular targeted therapy. 3) Revealed that activation of the mevalonate–geranylgeranyl diphosphate pathway contributes to chemoresistance in small cell lung cancer (SCLC), and proposed statin‑based combination therapy to overcome resistance. This work has led to the launch of three Investigator‑Initiated Trials (IITs). He has published more than 190 peer‑reviewed papers in high‑profile journals including Nature, Cell, Cancer Cell, Nature Genetics, Nature Cancer, with over 23,000 citations and an H‑index of 78. He is the recipient of numerous prestigious awards, including the Hundred Talents Program of the Chinese Academy of Sciences and the National Science Fund for Distinguished Young Scholars. He currently serves as Associate Editor for PLOS Genetics and Journal of Genetics and Genomics, and as an Editorial Board Member for Cancer Research, British Journal of Cancer, and Cancer Metastasis Reviews.