Abstract

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.

Highlights

  • Gastric adenocarcinoma (GAC) is the fifth most common cancer and the third leading cause of cancerrelated mortality worldwide [1]

  • Establishment of novel GAC cell lines from peritoneal carcinomatosis (PC) cells and Patientderived xenograft (PDX) Three PC cells were collected from volunteering patients with GAC and malignant ascites; and patient clinical characteristics including therapy, tumor types, site of metastases, and histopathology are listed in Supplemental Table 1

  • Both GA0518 and GA0825 cell lines were established from PDXs that were generated by a subcutaneous injection of donor PC cells (IP-013 and IP116) respectively

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Summary

Introduction

Gastric adenocarcinoma (GAC) is the fifth most common cancer and the third leading cause of cancerrelated mortality worldwide [1]. Peritoneal carcinomatosis (PC) is frequently identified in advanced GAC, and the 5-year survival rate of GAC with PC is < 5% [4]. Despite some progress in systemic therapy, the overall survival of GAC patients with PC has not improved appreciably [3, 5,6,7,8]. Much more in depth analysis is needed to discover novel targets/drugs for treating patients with PC. Gastric 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

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