NEW YORK – A team from China has demonstrated that the use of organoids established with patient tumor samples can provide a look at the multiomic factors linked to drug responses in hepatobiliary cancers affecting the liver or gallbladder.
"This comprehensive genomic analysis of hepatobiliary tumors has revealed the mutational spectrum and broadened our knowledge of the molecular events relevant to this fatal malignancy," senior author Lei Chen, with the Eastern Hepatobiliary Surgery Hospital, National Center for Liver Cancer, and the Ministry of Education in Shanghai, and colleagues wrote in Cell Reports Medicine on Thursday, adding that "much remains to be learned about the cancer genome and gene regulation in hepatobiliary tumors."
Starting with samples from nearly four dozen hepatocellular carcinoma cases, eight individuals with intrahepatic cholangiocarcinoma (ICC), four combined hepatocellular cholangiocarcinoma (CHC) cases, four gallbladder carcinoma (GBC) cases, one hilar cholangiocarcinoma (HCCA) cases, and one metastatic cancer case in China, the researchers successfully cultured 64 patient-derived hepatobiliary tumor organoids (PDHOs).
From there, they used a combination of genome sequencing, RNA sequencing, ATAC-seq-based chromatin accessibility profiling, and drug sensitivity screening to assess the PDHOs, highlighting interactions between specific mutations, gene regulation features, gene expression activity, and responses to 301 drugs with anti-cancer, metabolic, or epigenetic targets.
"Despite many potential therapeutic targets, the limited ability to accurately link genetic features with drug responses and precisely guide the clinical treatment of hepatobiliary tumors still makes their clinical outcome poor," the authors reasoned, noting that their PDHO lines "recapitulate tumoral histological and molecular features of their corresponding parental tumors."
Together, the analyses offered a look at pharmacogenomic features found in the hepatobiliary PDHOs, while unearthing related clues for modeling sensitivity to other drug treatments or for stratifying patient subpopulations by anticipated treatment effects, the authors explained.
"These results not only provide an annotated PDHO biobank of human liver cancer, but also suggest a systematic approach for obtaining a comprehensive understanding of the gene-regulatory network of liver cancer, advancing the applications of potential personalized medicine," they wrote, adding that their results "highlight the potential utility of PDHO models in basic and translational research."
In tumors containing noncoding alterations affecting the promoter region of the RUNX1 transcription factor-coding gene, for example, the team saw enhanced chromatin accessibility and a related rise in gene expression, along with enhanced sensitivity to the DNA topoisomerase I enzyme inhibitor drug irinotecan and several other drugs. The findings were supported by drug sensitivity testing on HCC-derived cell lines that were either missing or expressing higher-than-usual levels of RUNX1.
"Consistent with the findings observed in hepatobiliary tumor organoids, short-term growth inhibition assays revealed that RUNX1 knockdown cells were more resistant to irinotecan treatment in comparison with control cells," the authors reported. "Conversely, exogenous expression of RUNX1 rendered … cells more sensitive to irinotecan treatment."