Patient-derived Orthotopic Model Research Articles

Abstract 3725: Exosomal Galactin-3 promotes pre-metastatic niche formation that accelerates peritoneal metastases of gastric adenocarcinoma

Abstract Peritoneal carcinomatosis (PC) in gastric adenocarcinoma (GAC) lead to a short median survival (≤6 months). Pre-metastatic niche (PMN) formation, in a distant organ to prepare for tumor seeding and colonization, has long been recognized. However, the precise molecular and mechanistic contributions of exosomes in PMN formation of PC remain unclear. We identify that exosomes promote PMN formation in the peritoneal cavity by patient-derived orthotopic mouse model. Using an in-depth proteomic profiling of paired ascites cells and ascites-derived exosomes from PC patients, we discover that Galectin-3 as the exosomal payload is responsible for PC by promoting PMN formation in both patient-derived orthotopic model and syngeneic mouse model. Inhibition of exosomal Galectin-3 reverses PC. Furthermore, exosomal Galectin-3 activates cancer-associated fibroblasts (CAFs), which further activate the CXCL12/CXCR4 axis to orchestrate the immunosuppressive PMN. Simultaneous inhibition of exosomal Galectin-3, CXCR4, and PD-1 leads to tumor regression and durable anti-tumor responses. Thus, this study provides a rationale for the novel clinical strategy for GAC patients with PC. Citation Format: Yibo Fan, Shumei Song, Melissa Pool Pizzi, Katsuhiro Yoshimura, Jody V. Vykoukal, Samir Hanash, Jaffer Ajani. Exosomal Galactin-3 promotes pre-metastatic niche formation that accelerates peritoneal metastases of gastric adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3725.

Patient-derived cell lines and orthotopic mouse model of peritoneal carcinomatosis recapitulate molecular and phenotypic features of human gastric adenocarcinoma

BackgroundGastric adenocarcinoma with peritoneal carcinomatosis (PC) is therapy resistant and leads to poor survival. To study PC in depth, there is an urgent need to develop representative PC-derived cell lines and metastatic models to study molecular mechanisms of PC and for preclinical screening of new therapies.MethodsPC cell lines were developed from patient-derived PC cells. The tumorigenicity and metastatic potential were investigated by subcutaneously (PDXs) and orthotopically. Karyotyping, whole-exome sequencing, RNA-sequencing, and functional studies were performed to molecularly define the cell lines and compare genomic and phenotypic features of PDX and donor PC cells.ResultsWe established three PC cell lines (GA0518, GA0804, and GA0825) and characterized them in vitro. The doubling times were 22, 39, and 37 h for GA0518, GA0804, and GA0825, respectively. Expression of cancer stem cell markers (CD44, ALDH1, CD133 and YAP1) and activation of oncogenes varied among the cell lines. All three PC cell lines formed PDXs. Interestingly, all three PC cell lines formed tumors in the patient derived orthotopic (PDO) model and GA0518 cell line consistently produced PC in mice. Moreover, PDXs recapitulated transcriptomic and phenotypic features of the donor PC cells. Finally, these cell lines were suitable for preclinical testing of chemotherapy and target agents in vitro and in vivo.ConclusionWe successfully established three patient-derived PC cell lines and an improved PDO model with high incidence of PC associated with malignant ascites. Thus, these cell lines and metastatic PDO model represent excellent resources for exploring metastatic mechanisms of PC in depth and for target drug screening and validation by interrogating GAC for translational studies.

YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition

ObjectivePeritoneal carcinomatosis (PC; malignant ascites or implants) occurs in approximately 45% of advanced gastric adenocarcinoma (GAC) patients and associated with a poor survival. The molecular events leading to PC are...