Exosomal Galectin-3 promotes peritoneal metastases in gastric adenocarcinoma via microenvironment alterations
Yibo Fan,
Shumei Song,
Melissa Pool Pizzi,
Gengyi Zou,
Jody V. Vykoukal,
Katsuhiro Yoshimura,
Jiankang Jin,
George A. Calin,
Rebecca E. Waters,
Qiong Gan,
Linghua Wang,
Samir Hanash,
Shilpa S. Dhar,
Jaffer A. Ajani
Affiliations
Yibo Fan
Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Shumei Song
Coriell Institute for Medical Research, Camden, NJ 08103, USA
Melissa Pool Pizzi
Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Gengyi Zou
Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jody V. Vykoukal
Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Katsuhiro Yoshimura
Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
Jiankang Jin
Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
George A. Calin
Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Rebecca E. Waters
Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Qiong Gan
Department of Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Linghua Wang
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Samir Hanash
Department of Clinical Cancer Prevention, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Shilpa S. Dhar
Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
Jaffer A. Ajani
Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Corresponding author
Summary: Peritoneal carcinomatosis (PC) in gastric adenocarcinoma (GAC) is the most common metastatic site and leads to a short median survival. Exosomes have been shown to remodel the microenvironment, facilitating tumor metastases. However, the functional component in GAC cell-derived exosomes that remodel the landscape in the peritoneal cavity remains unclear. To address this, we performed in-depth proteomic profiling of ascites-derived exosomes from patients with PC, and we found that Galectin-3 was highly enriched in exosomes derived from malignant ascites. exosomal Galectin-3 was the crucial regulator of PC. Blockage of exosomal Galectin-3 significantly inhibited tumor metastases and prolonged overall survival. Exosomal Galectin-3 activated cancer-associated fibroblasts through integrin α1β1/FAK/Akt/mTOR/CXCL12 signaling. Combined inhibition of the CXCL12-CXCR4 axis and exosomal Galectin-3 enhanced the efficacy of anti-PD-1 immunotherapy, leading to significantly diminished PC progression and durable antitumor responses. These findings provide a rationale for clinical strategy of targeting exosomal Galectin-3 to treat PC.
