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<p>The tumor microenvironment (TME) has a profound influence on the progression of lung adenocarcinoma (LUAD) and its response to therapy. We identified a tumor-promoting communication network based on single-cell RNA sequencing. This shows an SPP1 + macrophage and basal epithelial cell communication module (CIM) that is enriched in invasive portions of tumors, and spatially associated with decreased cytotoxic T cell activity and poor prognosis. Transcriptomic modeling identified FAM117A as a major suppressor of the CIM network. FAM117A is a DYRK1A-interacting cell-cycle regulator. Loss of FAM117A resulted in longer G1/S transition time, increased cell proliferation, and an enhanced macrophage-epithelial feedback loop. Immunohistochemical studies showed decreased FAM117A expression in LUAD tissues, which correlated with SPP1 + macrophage density and poor outcome. Treatment with FAM117A or pharmacological inhibition of CDK4/6 reduced the in vitro and in vivo tumor growth. Thus, FAM117A links intrinsic cell cycle regulation with the extrinsic immune microenvironment, providing a rationale for combined therapies that address macrophage-tumor and cell cycle regulatory events in LUAD.</p>

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Single-cell profiling reveals FAM117A as a key regulator linking macrophage–epithelial crosstalk with the progression of lung adenocarcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月15日

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  • Chao Wu,
  • Zhipeng Ren,
  • Gang Che,
  • Hui Liu,
  • Haitao Tao,
  • Dan Li,
  • Jinliang Wang,
  • Xiaobin Hou,
  • Yi Hu

摘要

The tumor microenvironment (TME) has a profound influence on the progression of lung adenocarcinoma (LUAD) and its response to therapy. We identified a tumor-promoting communication network based on single-cell RNA sequencing. This shows an SPP1 + macrophage and basal epithelial cell communication module (CIM) that is enriched in invasive portions of tumors, and spatially associated with decreased cytotoxic T cell activity and poor prognosis. Transcriptomic modeling identified FAM117A as a major suppressor of the CIM network. FAM117A is a DYRK1A-interacting cell-cycle regulator. Loss of FAM117A resulted in longer G1/S transition time, increased cell proliferation, and an enhanced macrophage-epithelial feedback loop. Immunohistochemical studies showed decreased FAM117A expression in LUAD tissues, which correlated with SPP1 + macrophage density and poor outcome. Treatment with FAM117A or pharmacological inhibition of CDK4/6 reduced the in vitro and in vivo tumor growth. Thus, FAM117A links intrinsic cell cycle regulation with the extrinsic immune microenvironment, providing a rationale for combined therapies that address macrophage-tumor and cell cycle regulatory events in LUAD.