Single cell RNA sequencing of primary human hepatoblastoma tumoroids
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE233923 | GEO | 2024/09/12
REPOSITORIES: GEO
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Project description:Single cell RNA sequencing of primary human hepatoblastoma tumoroids
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Project description:Purpose: Advanced high-grade gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN) are highly aggressive and heterogeneous epithelial malignancies with poor clinical outcomes. No therapeutic predictive biomarkers exist and representative preclinical models to study their biology are missing. Patient-derived (PD) tumoroids may enable fast ex vivo pharmacotyping and provide subsidiary biological information for more personalized therapy strategies in individual patients. Experimental Design: PD tumoroids were established from rare biobanked surgical resections of advanced high-grade GEP-NEN patients. Using targeted in vitro pharmacotyping and next-generation sequencing of patient samples and matching PD tumoroids, we profiled individual patients and compared treatment-induced molecular stress response and in vitro drug sensitivity to the clinical therapy response. Results: We demonstrate high success rates in culturing PD tumoroids of high-grade GEP-NENs within clinically meaningful timespans. PD tumoroids recapitulate biological key features of high-grade GEP-NEN and mimic clinical response to cisplatin and temozolomide in vitro. Moreover, investigating treatment-induced molecular stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5A (KDM5A) and interferon-beta (IFNB1) as two vulnerabilities that act synergistically in combination with cisplatin and may present novel therapeutic options in high-grade GEP-NENs. Conclusion: Patient-derived tumoroids from high-grade GEP-NENs represent a relevant model to screen drug sensitivities of individual patients within clinically relevant timespans and provide novel functional insights into drug-induced stress responses. Clinical patient response to standard-of-care chemotherapeutics matches with drug sensitivities of PD tumoroids. Together, our findings provide a functional precision oncology approach for gathering patient-centered subsidiary treatment information that will potentially increase therapeutic opportunities in the framework of personalized medicine.
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Project description:To evaluate genetic similarities between tumoroids and the corresponding tumor tissues, we performed RNA sequencing of cells for each experimental condition. Since we injected human cancer cells into mice, cancer cells in the tumors were human while microenvironmental cells (i.e. Fibroblasts, Immune cells,…) were derived from mice. Thus, the RNA sequencing datasets generated from ACHN or 786-O tumor tissues (AxM and 7xM) and their respective tumoroids (AxTy and 7xTy) were mapped on human and mouse reference genome.
2023-06-30 | E-MTAB-12928 | biostudies-arrayexpress
Project description:Prostate cancer (PCa) is the second most common cancer in men and shows high inter- and intra-patient heterogeneity. Thus, treatment options are limited and there is a lack of representative preclinical models. Here we establish a biobank of murine organoids and tumoroids that reflect common patient mutations. The deletion of Pten alone, or in combination with Stat3, or Tp53, led to an upregulation of cancer-related pathways in organoids and in tissue-derived tumoroids. By performing a medium-throughput drug screen we identify two compounds, the PDPK1/AKT/FLT dual pathway inhibitor and tenovin-6, that effectively inhibited tumoroid growth. Additionally, these compounds inhibited the growth of several human PCa cell lines and could be used in combination with Enzalutamide. Overall, we provide evidence that murine tumoroids are versatile preclinical models for studying PCa tumorigenesis and drug sensitivities to develop novel therapeutic options for PCa patients.
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Project description:Tumoroids, sometimes referred to as cancer organoids, are patient-derived cancer cells grown as 3D, self-organized multicellular structures that maintain key characteristics (e.g., genotype, gene expression levels) of the tumors from which they originated. These models have emerged as valuable tools for studying tumor biology, cytotoxicity, and the response of patient-derived cells to cancer therapies. However, the establishment and maintenance of tumoroids have historically been challenging, labor-intensive, and highly variable from lab to lab, hindering their widespread use. Here, we established patient-derived colorectal cancer tumoroid lines in OncoPro Tumoroid Culture Medium and performed RNA profiling of single cells from primary dissociated tumors and the corresponding tumoroids to compare the transcriptomic concordance in primary and OncoPro-derived samples.
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Project description:The mechanisms underlying hepatoblastoma are not well defined. To address this, we generated transcriptomic profiles of normal, background, and hepatoblastoma liver samples from patients aged 0.01 months to 6 years, using RNA-sequencing. Hepatoblasoma was histologically confirmed. Here we focus on the elevation of stem cell markers and the loss of tumor suppressor proteins leading to the development of hepatoblastoma in very young children.
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Project description:To understand molecular mechanisms driving HB pathogenesis, we hypothesize that pathologic activation of Enhancer of Zeste Homolog 2 contributes to hepatoblastoma propagation. Here we demonstrate that EZH2 promotes proliferation in HB cell lines through interaction with β-catenin, the most frequently mutated gene in HB. We demonstrate that canonical and noncanonical EZH2 signaling occur in HB tumor cells, likely driven by aberrant EZH2 expression. We use comparison groups of liver cancer, hepatocytes, and dermal fibroblasts to establish the hepatoblastoma identity of our patient-derived cell lines.
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Project description:Hepatoblastoma (HB) is the most common primary liver malignancy of childhood. However, molecular investigations of the disease are limited and effective treatment options are lacking. The use of patient derived xenografts (PDX) to study biology and treatment strategies of HB has proven to be a useful tool. There is currently a knowledge gap in the investigation of key driver cells of HB in PDX models. Key driving pathways of HB tumor including WNT, AP-1, Hedgehog, Notch and MAPK pathways and genes such as GPC3, DLK1 and HMGA2 have been identified in primary HB tumor and PDX as integral players in HB tumor growth. Cell clusters have been defined with distinct roles in tumor development. Cell populations with initiating, angiogenic (endothelial), maintenance, and progression signatures have been identified in one HB patient tumor and corresponding PDX tumor. Critical pathways combined with identification of distinct cell populations within HB tumor will allow for investigation of novel treatment strategies in vitro and in vivo.
2021-07-29 | GSE180664 | GEO