Scholarlink

<p>Small cell lung cancer (SCLC) is a devastating disease with limited therapeutic advancements. Although SCLC has recently been classified into four molecular subtypes, subtype-specific therapies are still lacking. Here, we established 40 patient-derived SCLC organoid lines with predominant <i>TP53</i> and <i>RB1</i> alterations and rare targetable genetic lesions. Transcriptome profiling divided the SCLC organoids into neuroendocrine (NE)-type SCLC and non-NE-type SCLC, with the latter characterized by YAP1 or POU2F3 expression. NE-type SCLC organoids grew independent of alveolar niche factors, whereas non-NE-type SCLC organoids relied on insulin-like growth factor (IGF)-1-driven YAP1 and AP1 activation. Therapeutic targeting of IGF-1, YAP1 and AP1 effectively suppressed the growth of non-NE-type organoids. Co-knockout of <i>TP53</i> and <i>RB1</i> in human alveolar cells altered their lineage toward the airway epithelium-like fate and conferred IGF-1 dependency, validating the subtype-phenotype connection. Our SCLC organoid library represents a valuable resource for developing biology-based therapies and has the potential to reshape the drug discovery landscape.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

An organoid library unveils subtype-specific IGF-1 dependency via a YAP–AP1 axis in human small cell lung cancer

  • 期刊论文

  • 发表日期：

    2025年4月30日

查看全文
  • Takahiro Fukushima,
  • Kazuhiro Togasaki,
  • Junko Hamamoto,
  • Katsura Emoto,
  • Toshiki Ebisudani,
  • Akifumi Mitsuishi,
  • Kai Sugihara,
  • Taro Shinozaki,
  • Masahiko Okada,
  • Ayaka Saito,
  • Hatsuyo Takaoka,
  • Fumimaro Ito,
  • Lisa Shigematsu,
  • Yuki Ohta,
  • Sirirat Takahashi,
  • Mami Matano,
  • Yutaka Kurebayashi,
  • Keiko Ohgino,
  • Takashi Sato,
  • Ichiro Kawada,
  • Keisuke Asakura,
  • Tomoyuki Hishida,
  • Hisao Asamura,
  • Shinnosuke Ikemura,
  • Hideki Terai,
  • Kenzo Soejima,
  • Mayumi Oda,
  • Masayuki Fujii,
  • Koichi Fukunaga,
  • Hiroyuki Yasuda,
  • Toshiro Sato

摘要

Small cell lung cancer (SCLC) is a devastating disease with limited therapeutic advancements. Although SCLC has recently been classified into four molecular subtypes, subtype-specific therapies are still lacking. Here, we established 40 patient-derived SCLC organoid lines with predominant TP53 and RB1 alterations and rare targetable genetic lesions. Transcriptome profiling divided the SCLC organoids into neuroendocrine (NE)-type SCLC and non-NE-type SCLC, with the latter characterized by YAP1 or POU2F3 expression. NE-type SCLC organoids grew independent of alveolar niche factors, whereas non-NE-type SCLC organoids relied on insulin-like growth factor (IGF)-1-driven YAP1 and AP1 activation. Therapeutic targeting of IGF-1, YAP1 and AP1 effectively suppressed the growth of non-NE-type organoids. Co-knockout of TP53 and RB1 in human alveolar cells altered their lineage toward the airway epithelium-like fate and conferred IGF-1 dependency, validating the subtype-phenotype connection. Our SCLC organoid library represents a valuable resource for developing biology-based therapies and has the potential to reshape the drug discovery landscape.