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<p>Intratumoral heterogeneity is intrinsically comprised of molecular alterations of tumor cells and extrinsically from interconnections with microenvironments. This study explores the spatial heterogeneity of ovarian clear cell carcinoma (OCCC), a rare cancer with significance to East Asian women. We profile 21 primary-metastatic tumor pairs in a discovery cohort and 16 tumors in two validation cohorts using spatial transcriptomic (ST) platforms. Our integrative analysis revealed an inverse relationship between OXPHOS and inflammation along the EMT gradient. OCCC cells undergoing partial EMT have metabolic shifts and lose <i>LCN2</i> expression, possibly via concomitant down-regulation of <i>SOX9</i>. Conversely, <i>LCN2</i> expression correlated with OXPHOS-enriched tumor signature, low EMT, and better outcomes in OCCC. Single-cell ST profiling using CosMx further identifies nine spatially distinct cancer cell populations including the <i>LCN2</i>-high cancer subclone with a high epithelial score. <i>SOX9</i> induction could partially restore epithelial-ness in <i>LCN2</i>-low cells suggesting that plasticity in OCCC is achieved via transcriptional reprogramming. Our findings provide further insights into epithelial-mesenchymal plasticity and the adaptive interactions between cancer cells and their microenvironments in OCCC.</p>

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Spatial transcriptomic profiling of ovarian clear cell carcinoma reveals heterogeneity in OXPHOS and EMT gradients

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月8日

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  • Thang Truong Le,
  • Duncan Yi-Te Wang,
  • Sebastian Rui-Gu Yan,
  • Yi-Cian Chen,
  • Ko-Chen Chen,
  • Tuan Zea Tan,
  • Pei-Yu Chu,
  • Denis Ting-Hsian Chen,
  • Yi-Chia Chiu,
  • Jia-Yuh Sheu,
  • Sydney Rechie Necesario,
  • Chen-Hao Huang,
  • Jieru Ye,
  • Ya-Ting Tai,
  • Hsueh-Fen Juan,
  • Feng-Chiao Tsai,
  • Wei-Chou Lin,
  • Ying-Cheng Chiang,
  • Lin-Hung Wei,
  • Ruby Yun-Ju Huang

摘要

Intratumoral heterogeneity is intrinsically comprised of molecular alterations of tumor cells and extrinsically from interconnections with microenvironments. This study explores the spatial heterogeneity of ovarian clear cell carcinoma (OCCC), a rare cancer with significance to East Asian women. We profile 21 primary-metastatic tumor pairs in a discovery cohort and 16 tumors in two validation cohorts using spatial transcriptomic (ST) platforms. Our integrative analysis revealed an inverse relationship between OXPHOS and inflammation along the EMT gradient. OCCC cells undergoing partial EMT have metabolic shifts and lose LCN2 expression, possibly via concomitant down-regulation of SOX9. Conversely, LCN2 expression correlated with OXPHOS-enriched tumor signature, low EMT, and better outcomes in OCCC. Single-cell ST profiling using CosMx further identifies nine spatially distinct cancer cell populations including the LCN2-high cancer subclone with a high epithelial score. SOX9 induction could partially restore epithelial-ness in LCN2-low cells suggesting that plasticity in OCCC is achieved via transcriptional reprogramming. Our findings provide further insights into epithelial-mesenchymal plasticity and the adaptive interactions between cancer cells and their microenvironments in OCCC.