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<p>Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that commonly support cancer development and progression. Here we show that different cancer cells transfer mitochondria to fibroblasts in cocultures and xenograft tumors, thereby inducing protumorigenic CAF features. Transplantation of functional mitochondria from cancer cells induces metabolic alterations in fibroblasts, expression of CAF markers and release of a protumorigenic secretome and matrisome. These features promote tumor formation in preclinical mouse models. Mechanistically, the mitochondrial transfer requires the mitochondrial trafficking protein MIRO2. Its depletion in cancer cells suppresses mitochondrial transfer and inhibits CAF differentiation and tumor growth. The clinical relevance of these findings is reflected by the overexpression of <i>MIRO2</i> in tumor cells at the leading edge of epithelial skin cancers. These results identify mitochondrial transfer from cancer cells to fibroblasts as a driver of tumorigenesis and provide a rationale for targeting MIRO2 and mitochondrial transfer in different malignancies.</p>

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MIRO2-mediated mitochondrial transfer from cancer cells induces cancer-associated fibroblast differentiation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月28日

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  • Michael Cangkrama,
  • Huan Liu,
  • Xiaoyu Wu,
  • Josephine Yates,
  • James Whipman,
  • Christoph G. Gäbelein,
  • Mai Matsushita,
  • Luca Ferrarese,
  • Sibilla Sander,
  • Francesc Castro-Giner,
  • Simran Asawa,
  • Magdalena K. Sznurkowska,
  • Manfred Kopf,
  • Jörn Dengjel,
  • Valentina Boeva,
  • Nicola Aceto,
  • Julia A. Vorholt,
  • Sabine Werner

摘要

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment that commonly support cancer development and progression. Here we show that different cancer cells transfer mitochondria to fibroblasts in cocultures and xenograft tumors, thereby inducing protumorigenic CAF features. Transplantation of functional mitochondria from cancer cells induces metabolic alterations in fibroblasts, expression of CAF markers and release of a protumorigenic secretome and matrisome. These features promote tumor formation in preclinical mouse models. Mechanistically, the mitochondrial transfer requires the mitochondrial trafficking protein MIRO2. Its depletion in cancer cells suppresses mitochondrial transfer and inhibits CAF differentiation and tumor growth. The clinical relevance of these findings is reflected by the overexpression of MIRO2 in tumor cells at the leading edge of epithelial skin cancers. These results identify mitochondrial transfer from cancer cells to fibroblasts as a driver of tumorigenesis and provide a rationale for targeting MIRO2 and mitochondrial transfer in different malignancies.