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<p>Tumor protein p53 (<i>TP53</i>) is the most frequently mutated gene across many cancers and is associated with shorter overall survival in lung adenocarcinoma (LUAD). Here, to define how <i>TP53</i> mutations affect the LUAD tumor microenvironment (TME), we constructed a multiomic cellular and spatial atlas of 23 treatment-naive human lung tumors. We found that <i>TP53</i>-mutant malignant cells lose alveolar identity and upregulate highly proliferative and entropic gene expression programs consistently across LUAD tumors from resectable clinical samples, genetically engineered mouse models, and cell lines harboring a wide spectrum of <i>TP53</i> mutations. We further identified a multicellular tumor niche composed of <i>SPP1</i><sup>+</sup> macrophages and collagen-expressing fibroblasts that coincides with hypoxic, prometastatic expression programs in <i>TP53</i>-mutant tumors. Spatially correlated angiostatic and immune checkpoint interactions, including <i>CD274</i>–<i>PDCD1</i> and <i>PVR</i>–<i>TIGIT</i>, are also enriched in <i>TP53</i>-mutant LUAD tumors and likely engender a more favorable response to checkpoint blockade therapy. Our systematic approach can be used to investigate genotype-associated TMEs in other cancers.</p>

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A cellular and spatial atlas of TP53-associated tissue remodeling defines a multicellular tumor ecosystem in lung adenocarcinoma

  • 期刊论文

  • 发表日期：

    2025年10月7日

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  • William Zhao,
  • Thinh T. Nguyen,
  • Atharva Bhagwat,
  • Akhil Kumar,
  • Bruno Giotti,
  • Benjamin Kepecs,
  • Jason L. Weirather,
  • Navin R. Mahadevan,
  • Asa Segerstolpe,
  • Komal Dolasia,
  • Jamshid Abdul-Ghafar,
  • Naomi R. Besson,
  • Stephanie M. Jones,
  • Brian Y. Soong,
  • Chendi Li,
  • Sebastien Vigneau,
  • Michal Slyper,
  • Isaac Wakiro,
  • Mei-Ju Su,
  • Karla Helvie,
  • Allison Frangieh,
  • Judit Jane-Valbuena,
  • Orr Ashenberg,
  • Mark Awad,
  • Asaf Rotem,
  • Raphael Bueno,
  • Orit Rozenblatt-Rosen,
  • Kathleen Pfaff,
  • Scott Rodig,
  • Aaron N. Hata,
  • Aviv Regev,
  • Bruce E. Johnson,
  • Alexander M. Tsankov

摘要

Tumor protein p53 (TP53) is the most frequently mutated gene across many cancers and is associated with shorter overall survival in lung adenocarcinoma (LUAD). Here, to define how TP53 mutations affect the LUAD tumor microenvironment (TME), we constructed a multiomic cellular and spatial atlas of 23 treatment-naive human lung tumors. We found that TP53-mutant malignant cells lose alveolar identity and upregulate highly proliferative and entropic gene expression programs consistently across LUAD tumors from resectable clinical samples, genetically engineered mouse models, and cell lines harboring a wide spectrum of TP53 mutations. We further identified a multicellular tumor niche composed of SPP1+ macrophages and collagen-expressing fibroblasts that coincides with hypoxic, prometastatic expression programs in TP53-mutant tumors. Spatially correlated angiostatic and immune checkpoint interactions, including CD274–PDCD1 and PVR–TIGIT, are also enriched in TP53-mutant LUAD tumors and likely engender a more favorable response to checkpoint blockade therapy. Our systematic approach can be used to investigate genotype-associated TMEs in other cancers.