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<p>Intratumour heterogeneity represents the hierarchical integration of genetic, phenotypic and microenvironmental heterogeneity. Although single-cell sequencing has clarified genetic and phenotypic variability, the heterogeneity of nongenetic, microenvironmental factors remains elusive. Here, we developed T-AP1, a tumour-targeted probe tracking extracellular H<sub>2</sub>O<sub>2</sub>, which allows the visualization and characterization of tumour cells exposed to oxidative stress, a hallmark of cancer. T-AP1 identified actively budding intratumour regions as H<sub>2</sub>O<sub>2</sub>-rich microenvironments (H<sub>2</sub>O<sub>2</sub> hotspots), which were primarily established by neutrophils. Mechanistically, tumour cells exposed to H<sub>2</sub>O<sub>2</sub> underwent partial epithelial–mesenchymal transition through p38–MYC axis activation and migrated away from H<sub>2</sub>O<sub>2</sub> hotspots. This escape mechanism was absent in normal epithelial cells but prevalent in most cancers except NRF2-hyperactivated tumours, which exhibited abrogated p38 responses and enhanced antioxidant programmes, thus revealing an intrinsic stress defence programme in cancers. Together, T-AP1 enabled the identification of H<sub>2</sub>O<sub>2</sub> hotspots that provide a niche for cancer cell dissemination, offering insights into metastasis initiation.</p>

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Intratumour oxidative hotspots provide a niche for cancer cell dissemination

  • 期刊论文

  • 发表日期：

    2025年2月21日

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  • Yoshifumi Ueda,
  • Shigeki Kiyonaka,
  • Laura M. Selfors,
  • Keisuke Inoue,
  • Hiroshi Harada,
  • Tomohiro Doura,
  • Kunishige Onuma,
  • Makoto Uchiyama,
  • Ryuhei Kurogi,
  • Yuji Yamada,
  • Jiacheng H. Sun,
  • Reiko Sakaguchi,
  • Yuki Tado,
  • Haruki Omatsu,
  • Harufumi Suzuki,
  • Mike Aoun,
  • Takahiro Nakayama,
  • Taketoshi Kajimoto,
  • Tetsuya Yano,
  • Rikard Holmdahl,
  • Itaru Hamachi,
  • Masahiro Inoue,
  • Yasuo Mori,
  • Nobuaki Takahashi

摘要

Intratumour heterogeneity represents the hierarchical integration of genetic, phenotypic and microenvironmental heterogeneity. Although single-cell sequencing has clarified genetic and phenotypic variability, the heterogeneity of nongenetic, microenvironmental factors remains elusive. Here, we developed T-AP1, a tumour-targeted probe tracking extracellular H2O2, which allows the visualization and characterization of tumour cells exposed to oxidative stress, a hallmark of cancer. T-AP1 identified actively budding intratumour regions as H2O2-rich microenvironments (H2O2 hotspots), which were primarily established by neutrophils. Mechanistically, tumour cells exposed to H2O2 underwent partial epithelial–mesenchymal transition through p38–MYC axis activation and migrated away from H2O2 hotspots. This escape mechanism was absent in normal epithelial cells but prevalent in most cancers except NRF2-hyperactivated tumours, which exhibited abrogated p38 responses and enhanced antioxidant programmes, thus revealing an intrinsic stress defence programme in cancers. Together, T-AP1 enabled the identification of H2O2 hotspots that provide a niche for cancer cell dissemination, offering insights into metastasis initiation.