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<p>A central challenge in cancer research is to identify the secreted factors that sustain tumor cell survival. This is best exemplified in Hodgkin lymphoma, where malignant cells constitute a minor fraction of the tumor and rely on signals from the microenvironment for survival. Using genome-wide transcriptional profiling with spatial and single-cell resolution, we show that the neighborhood around malignant cells forms a distinct niche of 31 non-malignant cell types, enriched in helper T cells and myeloid cells, but depleted of plasma cells. Moreover, our spatial analysis nominates IL13 as a candidate survival factor. Recombinant IL13 augments malignant cell growth in vitro, and genome-wide loss-of-function screens across &gt;1000 human cancer cell lines identify IL4R and IL13RA1, heterodimeric components of the IL13 receptor, as uniquely essential in Hodgkin lymphoma. Importantly, blocking antibodies phenocopy genetic inactivation. Our findings provide a biological rationale for testing IL13-directed therapies, which are already FDA-approved, in Hodgkin lymphoma.</p>

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Genome-scale spatial mapping of the Hodgkin lymphoma microenvironment identifies tumor cell survival factors

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月20日

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  • Vignesh Shanmugam,
  • Neriman Tokcan,
  • Daniel Chafamo,
  • Sean Sullivan,
  • Mehdi Borji,
  • Haley Martin,
  • Gail Newton,
  • Naeem Nadaf,
  • Saoirse Hanbury,
  • Irving Barrera,
  • Dylan Cable,
  • Jackson Weir,
  • Orr Ashenberg,
  • Geraldine Pinkus,
  • Scott Rodig,
  • Caroline Uhler,
  • Evan Macosko,
  • Margaret Shipp,
  • Abner Louissaint Jr.,
  • Fei Chen,
  • Todd R. Golub

摘要

A central challenge in cancer research is to identify the secreted factors that sustain tumor cell survival. This is best exemplified in Hodgkin lymphoma, where malignant cells constitute a minor fraction of the tumor and rely on signals from the microenvironment for survival. Using genome-wide transcriptional profiling with spatial and single-cell resolution, we show that the neighborhood around malignant cells forms a distinct niche of 31 non-malignant cell types, enriched in helper T cells and myeloid cells, but depleted of plasma cells. Moreover, our spatial analysis nominates IL13 as a candidate survival factor. Recombinant IL13 augments malignant cell growth in vitro, and genome-wide loss-of-function screens across >1000 human cancer cell lines identify IL4R and IL13RA1, heterodimeric components of the IL13 receptor, as uniquely essential in Hodgkin lymphoma. Importantly, blocking antibodies phenocopy genetic inactivation. Our findings provide a biological rationale for testing IL13-directed therapies, which are already FDA-approved, in Hodgkin lymphoma.