Biology subjects

Lopez-Terrada, D.

Publications and source records attributed to Lopez-Terrada, D..

4 recordsLinked to original sources

bioRxiv2024

Asynchronous Transitions from Hepatoblastoma to Carcinoma in High-Risk Pediatric Tumors

BackgroundPediatric hepatocellular tumors are most commonly classified as hepatoblastoma (HB) or hepatocellular carcinoma (HCC), yet a subset exhibits mixed histological and molecular features of both. These tumors, previously described as hepatoblastomas with carcinoma features (HBCs), include cases provisionally designated by the World Health Organization as hepatocellular neoplasm-not otherwise specified (HCN-NOS). Their biology remains poorly understood, with unresolved questions about their cellular composition and outcomes. In particular, it is unclear whether HBCs comprise hybrid cell populations with combined HB and HCC characteristics (HBC cells) or admixtures of distinct HB and HCC cells. MethodsWe performed multi-omics profiling--including snRNA-seq, snDNA-seq, and multi-region longitudinal bulk RNA and DNA sequencing--to characterize HBC composition, evolution, and treatment response. ResultsHBCs comprise heterogeneous mixtures of HB-like, HBC-like, and HCC-like molecular cell types. HBC outcomes are significantly worse than HB, and HBC cells are more chemoresistant than HB cells, with resistance shaped by their cell identity, genetic alterations, and embryonic differentiation stage. HBC cells originate from HB cells that were arrested at early hepatic stem cell development stages because of aberrant WNT signaling activation. Inhibition of WNT signaling promoted differentiation and enhanced sensitivity to chemotherapy. Furthermore, each analyzed HBC reflected a dynamic process of multiple HB-to-HBC and HBC-to-HCC transitions, underscoring their evolutionary complexity. ConclusionsMulti-omics profiling of HBCs revealed key findings about their biology and composition, demonstrating that they originate from HB precursors at early hepatic stem cell development stages and that their differentiation arrest depends on sustained aberrant WNT-signaling activity.

genomics↗

bioRxiv2023

An indocyanine green-based liquid biopsy test for circulating tumor cells for pediatric liver cancer

Background and AimsHepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the most common malignant hepatocellular tumors seen in children. The aim of this work was to develop a liquid biopsy test for circulating tumor cells (CTCs) for these tumors that would be less invasive and provide information about the real-time state of tumors in response to therapies. MethodsFor this test, we utilized indocyanine green (ICG), a far-red fluorescent dye that is used clinically to identify malignant liver cells in the body during surgery. We assessed ICG accumulation in cell lines with fluorescence microscopy and flow cytometry. For our CTC test, we developed a panel of liver tumor-specific markers, ICG, Glypican-3 (GPC3), and DAPI and tested this panel with cell lines and non-cancer control blood samples. We then used this panel to analyze whole blood samples for CTC burden with a cohort of 14 HB and HCC patients and correlated with patient characteristics and outcomes. ResultsWe showed that ICG accumulation is specific to liver cancer cells, compared to non-malignant liver cells, non-liver solid tumor cells, and non-malignant cells and can be used to identify liver tumor cells in a mixed population of cells. Experiments with the ICG/GPC3/DAPI panel showed that it specifically tagged malignant liver cells. With patient samples, we found that CTC burden from sequential blood samples from the same patients mirrored the patients responses to therapy. ConclusionsOur novel ICG-based liquid biopsy test for CTCs can be used to specifically count CTCs in the blood of pediatric liver cancer patients. Impact and implicationsThis manuscript represents the first report of circulating tumor cells in the blood of pediatric liver cancer patients. The novel and innovative assay for CTCs shown in this paper will facilitate future work examining the relationship between CTC numbers and patient outcomes, forming the foundation for incorporation of liquid biopsy into routine clinical care for these patients. Graphical abstractOverview of novel liquid biopsy test for circulating tumor cells for pediatric liver cancer. Figure made with Biorender. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=39 SRC="FIGDIR/small/547557v1_ufig1.gif" ALT="Figure 1"> View larger version (10K): org.highwire.dtl.DTLVardef@3c62d0org.highwire.dtl.DTLVardef@7b5b59org.highwire.dtl.DTLVardef@aa6292org.highwire.dtl.DTLVardef@2d67ca_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Hepatoblastomas with carcinoma features (HBCs) represent a biological spectrum of aggressive neoplasms in children and young adults

Malignant hepatocellular cancers are the most common primary liver malignancies in children, and hepatoblastomas (HBs) account for more than two-thirds of these cases. While most HBs respond to chemotherapy and have favorable outcomes, the 3-year overall survival rate for high-risk HBs is below 50% and guidelines for their classification and treatment are still evolving. HB risk-stratification efforts using clinical, histological, and molecular parameters have been reported to help identify patients that require more or less aggressive therapies in retrospective studies, and are being validated in clinical trials. However, risk assessment is particularly challenging for cancers with certain histologies, including tumors in the recently proposed provisional hepatocellular neoplasm not otherwise specified (HCN NOS) category. HCN NOSs exhibit either intermediate or combined HB and hepatocellular carcinoma (HCC) histological features, and while neoplasms with such features were observed over a decade ago, only a handful have been characterized and little is known about their biology and clinical features. Here, we molecularly characterized a series of clinically annotated HCN NOSs that demonstrated either intermediate HB/HCC histology or distinct coexisting areas with HB and HCC histological features. In addition, molecular profiling of HBs demonstrating focal pleomorphism or anaplasia (HB FPA) revealed underlying biological features previously observed in HCCs. Our study suggested that HCN NOSs and HB FPAs are aggressive tumors, irrespective of patient age or resectability. Consequently, we designated them collectively as HBs with carcinoma features (HBCs) and outlined histological and molecular characteristics for their diagnosis and treatment. In our single-institution study, transplanted HBC patients were significantly and more than twice as likely to have good outcomes, highlighting the importance of molecular testing and aggressive early intervention.

cancer biology↗

bioRxiv2021

HepT1-derived murine models of high-risk hepatoblastoma display vascular invasion, metastasis, and circulating tumor cells

Hepatoblastoma (HB) is the most common pediatric primary liver malignancy, and survival for high-risk disease approaches 50%. Mouse models of HB fail to recapitulate hallmarks of high-risk disease. The aim of this work was to generate murine models that show high-risk features including multifocal tumors, vascular invasion, metastasis, and circulating tumor cells (CTCs). HepT1 cells were injected into the livers or tail veins of mice, and tumor growth was monitored with magnetic resonance and bioluminescent imaging. Blood was analyzed with fluorescence activated cell sorting to identify CTCs. Intra- and extra-hepatic tumor samples were harvested for immunohistochemistry and RNA and DNA sequencing. Cell lines were grown from tumor samples and profiled with RNA sequencing. With intrahepatic injection of HepT1 cells, 100% of animals grew liver tumors and showed vascular invasion, metastasis, and CTCs. Mutation profiling revealed genetic alterations in seven cancer-related genes, while transcriptomic analyses showed changes in gene expression with cells that invade vessels. Tail vein injection of HepT1 cells resulted in multifocal, metastatic disease. These unique models will facilitate further meaningful studies of high-risk HB. Summary StatementIn this work, we developed and thoroughly characterized several unique models of hepatoblastoma derived from the HepT1 cell line that show high-risk features.

cancer biology↗