Regulation of neuronal invasion of small cell lung cancer by STMN2/β-alanine-controlled metabolic reprogramming

  • Cell Rep. 2026 Mar 28;45(4):117208. doi: 10.1016/j.celrep.2026.117208.
Yan Zhou  1 ,  Runbo Zhong  1 ,  Yanwei Zhang  1 ,  Michael R Shurin  2 ,  Galina V Shurin  3 ,  Liwen Xiong  1 ,  Tianqing Chu  1 ,  Baohui Han  1 ,  Haohua Teng  4 ,  Yu Yang  5 ,  Erpeng Wu  5 ,  Chi Zhang  5 ,  Lincheng Zhang  1 ,  Wanting Liu  1 ,  Yuqing Lou  1 ,  Jun Lu  5 ,  Yongjie Wang  6 ,  Hua Zhong  7
Affiliations
  • 1. Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 2. Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
  • 3. Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • 4. Department of Pathology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 5. Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China; Shanghai Key Laboratory of Thoracic Tumor Biotherapy, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China.
  • 6. School of Pharmacy, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China. Electronic address: [email protected].
  • 7. Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China. Electronic address: [email protected].
PMID: 41904954 DOI: 10.1016/j.celrep.2026.117208
Abstract

Small Cell Lung Cancer (SCLC) exhibits a high incidence of perineural invasion (PNI), a clinical feature associated with poor prognosis. Here, we establish PNI as an independent adverse prognostic factor in a surgical SCLC cohort. We further show that the neural microenvironment upregulates stathmin-2 (STMN2) in SCLC cells. STMN2, in a concentration-dependent manner, activates the β-alanine metabolic pathway, leading to intracellular β-alanine accumulation, which enhances tumor cell migration and invasion. In vivo, STMN2 knockdown suppresses neural invasion, an effect reversible upon β-alanine supplementation. This work defines a neural-STMN2-β-alanine-invasion axis that drives PNI in SCLC, providing mechanistic insights and highlighting a promising metabolic vulnerability for therapeutic intervention.

Keywords
CP: cancer; CP: neuroscience; SCLC; invasiveness; perineural invasion; stathmin-2.
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