イヌの血管肉腫の新規患者由来モデルを樹立～糖が乏しい環境で働くリジンラクチル化の新たな役割を発見～

2026-02-13

2026-02-12 北海道大学

北海道大学大学院獣医学研究院の研究グループは、イヌ血管肉腫の新規培養細胞株2株と患者腫瘍由来異種移植(PDX)モデル3株を樹立した。これらは腫瘍本来の性質を保持し、基礎研究基盤を大きく拡充する成果である。さらに、グルコース欠乏条件下ではタンパク質修飾であるリジンラクチル化が全体として減少する一方、転写開始点付近に集積し、ATF4を介したストレス応答遺伝子群の制御に関与することを解明した。本成果はFrontiers in Veterinary Scienceに掲載され、ヒト血管肉腫との共通病態理解や治療法開発への応用が期待される。

図 1. 血管肉腫研究モデルの樹立

<関連情報>

イヌ血管肉腫では、グルコース欠乏下でリジンラクチル化がATF4介在性ストレス応答を制御する
Lysine lactylation regulates ATF4-mediated stress responses under glucose starvation in canine hemangiosarcoma

Tamami Suzuki,Kazuki Heishima,Jumpei Yamazak,Masaya Yamazaki,Ryohei Kinoshita,Sangho Kim,Kenji Hosoya,Yuko Okamatsu-Ogura,Michihito Sasaki,Peng Xu^;;Qin Yan,Takashi Kimura,Keisuke Aoshima
Frontiers in Veterinary Science Published:12 February 2026
DOI:https://doi.org/10.3389/fvets.2026.1734339

Excess lactate is produced in tumor cells by aerobic glycolysis and regulates gene expressions by histone lactylation. However, how histone lactylation functions under glucose-limited conditions remains unknown. Here, we show that lysine lactylation redistributes to transcription start sites (TSSs) during glucose deprivation, thereby altering biological behaviors in canine hemangiosarcoma (HSA) cells. Glucose deprivation significantly decreased global histone lactylation levels, while lactylation peaks were enriched at TSSs of ATF4-regulated stress-response, asparagine-synthesis and immune-related genes. Stress-response gene expressions were upregulated, and ATF4 polyclonal knockout abrogated this activation. [U-¹³C]glutamine tracing demonstrated that HSA cells synthesized asparagine from glutamine when glucose was scarce, and asparagine supplementation modestly activated cell proliferation. In HSA patient tissues, H3K18la levels were heterogeneous, and M2-like macrophages preferentially infiltrated tumor regions showing low histone lactylation levels. These findings demonstrate that lysine lactylation regulates transcription that supports tumor cell survival and fosters a pro-tumor microenvironment even under glucose-limited conditions.