Arachidonic acid released by PIK3CA mutant tumor cells triggers malignant transformation of colonic epithelium by inducing chromatin remodeling

Baoyu He; Qingli Bie; Rou Zhao; Yugang Yan; Guanjun Dong; Baogui Zhang; Sen Wang; Wenrong Xu; Dongxing Tian; Yujun Hao; Yanhua Zhang; Mingsheng Zhao; Huabao Xiong; Bin Zhang

doi:10.1016/j.xcrm.2024.101510

Arachidonic acid released by PIK3CA mutant tumor cells triggers malignant transformation of colonic epithelium by inducing chromatin remodeling

Cell Rep Med. 2024 Apr 5:101510. doi: 10.1016/j.xcrm.2024.101510. Online ahead of print.

Authors

Baoyu He¹, Qingli Bie¹, Rou Zhao², Yugang Yan³, Guanjun Dong⁴, Baogui Zhang⁵, Sen Wang², Wenrong Xu⁶, Dongxing Tian², Yujun Hao⁷, Yanhua Zhang⁷, Mingsheng Zhao⁴, Huabao Xiong⁸, Bin Zhang⁹

Affiliations

¹ Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China; School of Integrative Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250355, China.
² Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China.
³ School of Medical Engineering, Jining Medical University, Jining, Shandong 272067, China.
⁴ Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong 272067, China.
⁵ Department of Gastrointestinal Surgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China.
⁶ Key Laboratory of Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212000, China.
⁷ State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.
⁸ Institute of Immunology and Molecular Medicine, Jining Medical University, Jining, Shandong 272067, China. Electronic address: xionghbl@163.com.
⁹ Department of Laboratory Medicine, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272000, China. Electronic address: zhangbin@mail.jnmc.edu.cn.

PMID: 38614093
DOI: 10.1016/j.xcrm.2024.101510

Abstract

Key gene mutations are essential for colorectal cancer (CRC) development; however, how the mutated tumor cells impact the surrounding normal cells to promote tumor progression has not been well defined. Here, we report that PIK3CA mutant tumor cells transmit oncogenic signals and result in malignant transformation of intestinal epithelial cells (IECs) via paracrine exosomal arachidonic acid (AA)-induced H3K4 trimethylation. Mechanistically, PIK3CA mutations sustain SGK3-FBW7-mediated stability of the cPLA2 protein, leading to the synthetic increase in AA, which is transported through exosome and accumulated in IECs. Transferred AA directly binds Menin and strengthens the interactions of Menin and MLL1/2 methyltransferase. Finally, the combination of VTP50469, an inhibitor of the Menin-MLL interaction, and alpelisib synergistically represses PDX tumors harboring PIK3CA mutations. Together, these findings unveil the metabolic link between PIK3CA mutant tumor cells and the IECs, highlighting AA as the potential target for the treatment of patients with CRC harboring PIK3CA mutations.

Keywords: H3K4 trimethylation; Menin; PIK3CA mutations; VTP50469; arachidonic acid; cPLA2; exosome; intestinal epithelial cells; malignant transformation.