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Studying Molecular Subtypes of Peritoneal Metastases in Gastric Cancer

Use of purified tumour cells from ascites and their corresponding cell lines as the resource for genomic analyses
06 Sep 2021
Gastrointestinal cancers;  Translational research

In a study published on 16 August 2021 in the Nature Cancer, the research team led by Yosuke Tanaka and Fumiko Chiwaki of the Division of Cellular Signalling, National Cancer Centre Research Institute in Tokyo, Japan took advantage of cancer cells purified from malignant ascites and established corresponding cell lines as the resources for genomic analyses to overcome the technical limitations associated with analyses of primary tumours. A comprehensive multiomic analysis of malignant ascitic fluid samples and their corresponding tumour cell lines from 98 patients with gastric cancer and peritoneal metastases, including whole genome sequencing, RNA sequencing, DNA methylation and enhancer landscape identified multiple molecular targets enriched in this tumour type and stratified it into two distinct molecular subtypes suggesting a potential molecular-guided therapeutic strategy.

The authors explained in the study background that peritoneal metastases and subsequent development of malignant ascites is the most frequent cause of death in patients with advanced gastric cancer, especially those with diffuse type gastric cancer. Next-generation sequencing has revealed some of the genetic alterations and provided a possible path to treatment with anti-HER2 therapy or immune checkpoint inhibitors. However, the benefit of molecular targeting therapies is limited to only a small subset of patients and effective treatment strategies are still uncertain for gastric cancer with malignant ascites.

Genomic characterisation has rarely been conducted in patients with gastric cancer and malignant ascites. The characterisation of this tumour type is hampered by the high stromal content in primary tumour samples, making it difficult to precisely estimate transcriptomic, epigenetic and genomic alterations of pure cancer cells. Furthermore, only a small number of diffuse type gastric cancer cell lines are currently available, so drug sensitivity has not been extensively studied.

In this study, the researchers obtained malignant ascitic fluid samples from 106 patients with metastatic gastric cancer. Tumour cells were purified from the ascitic fluid of 76 patients whose peripheral blood mononuclear cells (PMBCs) were available. They also established gastric cancer cell lines from malignant ascites from 59 individuals and purified cancer cells were available for 37 of these patients. A total of 233 samples comprising of 76 purified tumour cells, 98 matched PBMCs and 59 cell lines from 98 patients were subjected to whole genome sequencing. Purified tumour samples and cell lines were also analyzed with RNA sequencing.

The tumour contents of purified cancer cells from ascites obtained from whole genome sequencing guaranteed their high purity and clonality analysis revealed that tumour cells comprised mostly one dominant clone or a few subclones. Pairwise analyses of the tumour cells and corresponding cell lines showed that the latter closely recapitulated the features of the former in terms of somatic mutations. Gene expression levels were also positively correlated. The study team observed a few cases with apparent discrepancies in mutations and transcriptome profiles.

Overall, the researchers identified a higher frequency of receptor tyrosine kinase and mitogen-activated protein kinase pathway alterations compared to primary gastric cancer with approximately half of the gene alterations being potentially treatable with targeted therapy.

The analyses stratified ascites-disseminated gastric cancer into two distinct molecular subtypes, one displaying active super enhancers at the ELF3, KLF5 and EHF loci, and a second subtype bearing TGF-β pathway activation through SMAD3 super enhancer activation and high expression of TEAD1. In the TGF-β subtype, inhibition of the TEAD pathway circumvents therapy resistance, suggesting a potential molecular-guided therapeutic strategy for this subtype.

The authors concluded that their comprehensive genomic study with integrated analyses using whole genome sequencing, transcriptome analyses (RNA sequencing), ChIP sequencing and methylation analyses resulted in the identification of multiple molecular targets enriched in gastric cancer with peritoneal metastases and revealed a subgroup of patients with an active TGF-β circuit and explored the potential of targeting TEAD family proteins to overcome therapeutic resistance to targeting agents.

Peritoneal metastases are hallmark of incurable advanced gastric cancer and this study of molecular features represents an important attempt in a tumour entity with currently no available curative treatment.

The study was supported in part by grants from the Project for Cancer Research and Therapeutic Evolution, funding for research to expedite effective drug discovery by Government, Academia and Private partnership and Leading Advanced Projects for Medical Innovation grant from the Japan Agency for Medical Research and Development.

Reference

Tanaka Y, Chiwaki F, Kojima S, et al. Multiomic profiling of peritoneal metastases in gastric cancer identifies molecular subtypes and therapeutic vulnerabilities. Nature Cancer; Published online 16 August 2021. DOI: https://doi.org/10.1038/s43018-021-00240-6

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