2. Academic Validation
  3. Cancer-associated fibroblast-derived extracellular vesicles regulate lipophagy through PLIN2 to modulate dormancy in salivary gland adenoid cystic carcinoma cells

Cancer-associated fibroblast-derived extracellular vesicles regulate lipophagy through PLIN2 to modulate dormancy in salivary gland adenoid cystic carcinoma cells

  • Exp Mol Med. 2025 Dec 18. doi: 10.1038/s12276-025-01600-3.
Zhichao Dou # 1,  Xu Zhang # 2,  Kun Meng 3,  Mao Li 1,  Xin Pang 2,  Wanli Wang 2,  Rongjia Shi 1,  Xinhua Liang 4,  Yaling Tang 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Sichuan, China.
  • 2 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Sichuan, China.
  • 3 Department of Stomatology, The General Hospital of Western Theater Command PLA, Chengdu, China.
  • 4 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Sichuan, China. [email protected].
  • 5 State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Department of Oral Pathology, West China Hospital of Stomatology, Sichuan University, Sichuan, China. [email protected].
  • # Contributed equally.
PMID: 41408408 DOI: 10.1038/s12276-025-01600-3
Abstract

Tumor recurrence and metastasis are largely attributed to dormant tumor cells receiving reactivation signals, particularly those originating from the tumor microenvironment. However, the detailed mechanisms of dormant tumor cell reactivation in salivary gland adenoid cystic carcinoma (SACC) remain largely unknown. Here our data revealed that Autophagy is activated in dormant SACC cells but becomes downregulated once these cells are reactivated, and that cancer-associated fibroblast (CAF)-mediated Autophagy promotes dormant SACC cells to resume proliferation and escape dormancy. Mechanistically, PLIN2 encapsulated in CAFs-derived extracellular vesicles promoted the initial stage of Autophagy through the endoplasmic reticulum stress signaling pathway, and directly bound to p62 to promote lipid droplet degradation through the lipophagy pathway, which provided energy for the reactivation of dormant SACC cells. Moreover, we confirmed that PLIN2 expression was remarkably correlated with poor survival in patients with SACC. Finally, we verified that the combination of tozasertib and PLIN2 was stable through molecular docking and molecular dynamics simulation, indicating that tozasertib has the potential to serve as a targeted PLIN2 drug for CAFs in SACC. Our findings suggest that targeting PLIN2 and Autophagy inhibition as part of primary SACC treatment may effectively eliminate dormant tumor cells and prevent SACC recurrence.

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