Livers are astounding organs that regulate our bodies metabolism and detoxifies our blood. The liver is made of several different cell types that each have specialized jobs and when we are healthy each cell does its job exceedingly well and the entire organ works like a well oiled machine. Sometimes, when diseases affect the liver, cells no longer perform their jobs well and undergo what are called transformations. This blurs the lines between the different types of cells that make up our livers and the machine stalls, leaving our liver unable to perform its important jobs. As more and more cells undergo transformation, there is a higher likelihood of developing one or both of two types of cancer: hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). HCC, emerging as the more prevalent of the two, is rooted in an array of chronic liver conditions, from viral hepatitis to metabolic syndromes. On the other side, CCA, though less common, casts a shadow with grim survival rates. Central to the battle between these two cancers developing is a molecular switch controlled by the oncogene MYC, which determines a cell’s allegiance to either HCC or CCA, influenced by transcription factors (TFs)—the unseen puppet masters of cellular fate.

Led by Dr. Amanda Craig and Dr. Xin Wei Wang from the National Cancer Institute (NIH), a pioneering study published in Cell Reports ventures deep into the genetic intricacies of primary liver cancer. Utilizing single-cell assay for transposase accessible chromatin sequencing (scATAC-seq), the research team set out to explore the transcriptional dynamics of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), unveiling distinct transcription factor (TF) activities that characterize these subtypes.

“Primary liver cancer is primarily divided into hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). The role of transcription factors (TFs) in guiding the malignant progression between HCC and iCCA is not thoroughly understood,” Dr. Craig clarified. Through detailed analysis of chromatin profiles from patient cells, the study painted a comprehensive picture of the cellular composition in liver cancer and identified TFs that sharply distinguish HCC from iCCA, thus shedding light on their unique genetic regulatory mechanisms.

“To deeply examine chromatin accessibility and genetic regulation in primary liver cancer, we performed scATAC-seq across a selection of patients, predominantly those with HCC and a few with iCCA. We evaluated the chromatin accessibility profiles from thousands of cells that passed our rigorous quality checks,” Dr. Craig detailed. The insights gained from this investigation not only advanced our understanding of liver cancer’s genetic framework but also highlighted the prognostic importance of the POU TF family in iCCA, linking its presence to adverse patient outcomes.

“In our analysis, the POU  TF family exhibited a widerange of expression in liver tumors. The POU TF family’s presence was more pronounced in tumors with TP53 mutations and was significantly correlated  with a reduced survival rate,” Dr. Craig further elaborated.

Despite notable advances in treatment, liver cancer remains a leading cause of cancer-related mortality globally. Dr. Craig and colleagues emphasizes the urgent need to unravel the distinct developments of these malignancies to enhance treatment efficacy. Their research illuminated the varied transcriptional landscapes within liver cancer, demonstrating the specific roles of nuclear receptors and ETS transcription factor families in differentiating HCC from iCCA. While some transcription factor families were prevalent in both HCC and iCCA, their association with prognostic factors was subtype-specific, suggesting their influence on cancer progression depends on specific cellular characteristics. Dr. Craig and her team’s findings offer valuable insights into the transcriptional mechanisms driving liver cancer, indicating potential therapeutic targets that could positively impact patient outcomes. Future research is poised to explore therapeutic vulnerabilities linked to aberrant transcription factor activity, marking a significant stride towards personalized treatment for liver cancer patients.


Craig et al., “Genome-wide profiling of transcription factor activity in primary liver cancer using single-cell ATAC sequencing,” Cell Reports.