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Cancer-Specific RNA Modifications in Tumour-Derived Extracellular Vesicles Promote Tumour Growth

Yuya Monoe1, Kentaro Jingushi1, Kohei Taniguchi2

  • 1Laboratory of Molecular and Cellular Physiology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Journal of Extracellular Vesicles
|May 6, 2025
PubMed

Insights

Cancer cells release extracellular vesicles (EVs) with altered RNA modifications, like N6-methyladenosine (m6A), that promote tumor growth by influencing immune cells. Restoring m6A levels in EVs suppressed tumor progression.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Immunology

Background:

  • RNA modifications are vital for cellular functions, and their dysregulation is implicated in diseases such as cancer.
  • Extracellular vesicles (EVs) carry various RNAs, but detecting RNA modifications within them is challenging due to limited RNA quantities.
  • Investigating RNA modifications in EVs is crucial for understanding cancer progression and developing new diagnostic or therapeutic strategies.

Purpose of the Study:

  • To develop a method for detecting RNA modifications in EVs.
  • To investigate the role of N6-methyladenosine (m6A) and tRNA fragments in cancer-derived EVs.
  • To elucidate the mechanism by which cancer-derived EVs promote tumor progression via immune cell modulation.

Main Methods:

  • Utilized a proprietary ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) system to detect RNA modifications in EVs.
  • Quantified N6-methyladenosine (m6A) levels in EVs from colon cancer and normal tissues.
  • Performed RNA sequencing to analyze tRNA fragments, including m6A-modified fragments, in cancer-derived EVs.
  • Investigated the functional impact of cancer-derived EVs on macrophage cytokine secretion and tumor cell proliferation.
  • Assessed the effect of manipulating m6A levels in EVs and depleting macrophages on tumor growth.

Main Results:

  • Successfully detected 22 distinct RNA modifications in EVs.
  • Identified significantly reduced levels of m6A in EVs from colon cancer tissues, correlating with cancer recurrence.
  • Demonstrated that increasing m6A levels in EVs by knocking out the Alkbh5 gene suppressed the tumor-promoting effects of colorectal cancer EVs.
  • Showed that cancer-derived EVs enhance pro-inflammatory cytokine secretion (TNF-α, IL-6) by macrophages in an m6A-dependent manner, promoting cancer cell proliferation.
  • Found elevated levels of 5'-half-tRNA fragment (5'-half)-GlyGCC and reduced m6A-modified 5'-half-GlyGCC in colorectal cancer EVs, which promoted tumor growth, an effect reduced by macrophage depletion.

Conclusions:

  • Cancer-specific RNA modifications exist within EVs and play a significant role in promoting tumor progression.
  • Reduced m6A levels in cancer-derived EVs contribute to tumor growth by modulating immune cell responses.
  • EV-mediated transfer of specific RNA fragments, like 5'-half-GlyGCC, influences tumor development.
  • Targeting RNA modifications in EVs or their interaction with immune cells presents a potential therapeutic avenue for cancer treatment.
Keywords:
5′‐half‐GlyGCCRNA modificationcolorectal cancerextracellular vesiclesinflammatory cytokines

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