2. Academic Validation
  3. Gastric cancer cell-originated small extracellular vesicle induces metabolic reprogramming of BM-MSCs through ERK-PPARγ-CPT1A signaling to potentiate lymphatic metastasis

Gastric cancer cell-originated small extracellular vesicle induces metabolic reprogramming of BM-MSCs through ERK-PPARγ-CPT1A signaling to potentiate lymphatic metastasis

  • Cancer Cell Int. 2023 May 9;23(1):87. doi: 10.1186/s12935-023-02935-5.
Jiaying Huang 1,  Xiang Wang 1,  Jing Wen 1,  Xinxin Zhao 1,  Chen Wu 1,  Lin Wang 1,  Xiaoli Cao 2,  Haibo Dong 3,  Xuejing Xu 4,  Feng Huang 1 5 6,  Wei Zhu 1,  Mei Wang 7
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu Province, China.
  • 2 Department of Laboratory Medicine, Affiliated Tumor Hospital of Nantong University, Nantong, Jiangsu Province, China.
  • 3 Department of Hematology, Nanjing Drum Tower Hospital, Affiliated Hospital of Jiangsu University, 321 Zhongshan Road, Gulou District, Nanjing, Jiangsu Province, China.
  • 4 Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Jiangsu University, 321 Zhongshan Road, Gulou District, Nanjing, Jiangsu Province, China.
  • 5 Department of Clinical Laboratory, Affiliated Kunshan Hospital of Jiangsu University, Suzhou, Jiangsu Province, China.
  • 6 Department of Clinical Laboratory, Maternal and Child, Health Care Hospital of Kunshan, Suzhou, Jiangsu Province, China.
  • 7 Department of Laboratory Medicine, School of Medicine, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu Province, China. wangmei8417@163.com.
PMID: 37158903 DOI: 10.1186/s12935-023-02935-5
Abstract

Tumor microenvironment and metabolic reprogramming are critical for tumor metastasis. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are widely involved in the formation of tumor microenvironment and present oncogenic phenotypes to facilitate lymph node metastasis (LNM) in response to small extracellular vesicles (sEV) released by gastric Cancer (GC) cells. However, whether metabolic reprograming mediates transformation of BM-MSCs remains elusive. Herein, we revealed that the capacity of LNM-GC-sEV educating BM-MSCs was positively correlated with the LNM capacity of GC cells themselves. Fatty acid oxidation (FAO) metabolic reprogramming was indispensable for this process. Mechanistically, CD44 was identified as a critical cargo for LNM-GC-sEV enhancing FAO via ERK/PPARγ/CPT1A signaling. ATP was shown to activate STAT3 and NF-κB signaling to induce IL-8 and STC1 secretion by BM-MSCs, thereby in turn facilitating GC cells metastasis and increasing CD44 levels in GC cells and sEV to form a persistent positive feedback loop between GC cells and BM-MSCs. The critical molecules were abnormally expressed in GC tissues, sera and stroma, and correlated with the prognosis and LNM of GC patients. Together, our findings uncover the role of metabolic reprogramming mediated BM-MSCs education by LNM-GC-sEV, which presents a novel insight into the mechanism underlying LNM and provides candidate targets for GC detection and therapy.

Keywords

Gastric cancer; Lymph node metastasis; Mesenchymal stem cells; Small extracellular vesicles.

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