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<p>Pulmonary pleomorphic carcinoma (PPC) is a rare subtype of lung cancer that comprises both epithelial and sarcomatoid components. The molecular basis of PPC, including the cellular dynamics of its components, remains largely unknown. To elucidate potential therapeutic targets for PPC, we perform a multi-omics analysis incorporating digital spatial profiling and single-cell RNA sequencing (scRNA-seq). PPC exhibits diverse driver gene alterations, including MET exon 14 skipping mutation (METex14) and ALK fusion. In spatial transcriptomics, MET gene and protein are overexpressed exclusively within the epithelial component and not in the sarcomatoid component, even in patients harboring METex14. Epithelial-mesenchymal transition (EMT)-related transcriptional changes, along with extracellular matrix (ECM) remodeling between the epithelial and sarcomatoid components, are observed. scRNA-seq identifies cell populations within the epithelial component that contribute to the malignant transformation and differentiation of the sarcomatoid component. They are characterized by an intermediate EMT state with ECM remodeling signature, suggesting their potential as novel therapeutic targets for PPC.</p>

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Single-cell and spatial transcriptomic characterization of pulmonary pleomorphic carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月16日

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  • Atsushi Matsuoka,
  • Kazuhiko Shien,
  • Shuta Tomida,
  • Masayoshi Ohki,
  • Kazuya Hisamatsu,
  • Ryota Fujiwara,
  • Kosei Ishimura,
  • Ryunosuke Fujii,
  • Tomoaki Higashihara,
  • Naohiro Hayashi,
  • Kazuhiro Okada,
  • Ryo Yoshichika,
  • Fumiaki Mukohara,
  • Mao Yoshikawa,
  • Yuma Fukumoto,
  • Ken Suzawa,
  • Yasuaki Tomioka,
  • Shin Tanaka,
  • Kentaroh Miyoshi,
  • Mikio Okazaki,
  • Seiichiro Sugimoto,
  • Yusuke Otani,
  • Atsushi Tanaka,
  • Hirofumi Inoue,
  • Yosuke Togashi,
  • Hidetaka Yamamoto,
  • Daisuke Ennishi,
  • Shinichi Toyooka

摘要

Pulmonary pleomorphic carcinoma (PPC) is a rare subtype of lung cancer that comprises both epithelial and sarcomatoid components. The molecular basis of PPC, including the cellular dynamics of its components, remains largely unknown. To elucidate potential therapeutic targets for PPC, we perform a multi-omics analysis incorporating digital spatial profiling and single-cell RNA sequencing (scRNA-seq). PPC exhibits diverse driver gene alterations, including MET exon 14 skipping mutation (METex14) and ALK fusion. In spatial transcriptomics, MET gene and protein are overexpressed exclusively within the epithelial component and not in the sarcomatoid component, even in patients harboring METex14. Epithelial-mesenchymal transition (EMT)-related transcriptional changes, along with extracellular matrix (ECM) remodeling between the epithelial and sarcomatoid components, are observed. scRNA-seq identifies cell populations within the epithelial component that contribute to the malignant transformation and differentiation of the sarcomatoid component. They are characterized by an intermediate EMT state with ECM remodeling signature, suggesting their potential as novel therapeutic targets for PPC.