Dataset Information

Organoid Models of Human Liver Cancers Derived from Tumor Needle Biopsies

ABSTRACT: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second cause of cancer-related mortality worldwide. HCC mainly arises in livers with pre-existing underlying diseases including viral hepatitis, alcoholic liver disease and nonalcoholic steatohepatitis. The multikinase inhibitor Sorafenib is the only drug available for the treatment of advanced HCC. However, due to the different backgrounds and the resulting heterogeneity of tumors, its efficacy greatly varies between patients and is further limited due to adverse effects and the development of drug resistance. Current in vitro models to study HCC based on pre-existing cancer cell lines fail in recapitulating key features such as tumor architecture, cellular heterogeneity and cell-cell interactions. In this study we report the generation of long-term three-dimensional organoid cultures from tumor biopsies of HCC patients with different etiologies and tumor stages. We demonstrate that HCC organoids retain the morphology and histological grading of the primary tumor as well as the expression pattern of HCC tumor markers. Moreover, whole exome sequencing analyses demonstrated that HCC organoids preserve the genetic heterogeneity present in their original tumors. Finally, in proof-of-principle studies we show that liver cancer organoids can be used to test sensitivity to Sorafenib. In conclusion, organoid models can be derived from needle biopsies of liver cancers, preserve the original tumor characteristics and provide a novel tool for developing tailored therapies urgently needed for a frequent malignancy with limited treatment options.

PROVIDER: EGAS00001003115 | EGA |

REPOSITORIES: EGA

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Organoid Models of Human Liver Cancers Derived from Tumor Needle Biopsies.

Nuciforo Sandro S Fofana Isabel I Matter Matthias S MS Blumer Tanja T Calabrese Diego D Boldanova Tujana T Piscuoglio Salvatore S Wieland Stefan S Ringnalda Femke F Schwank Gerald G Terracciano Luigi M LM Ng Charlotte K Y CKY Heim Markus H MH

Cell reports 20180701 5

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second most frequent cause of cancer-related mortality worldwide. The multikinase inhibitor sorafenib is the only treatment option for advanced HCC. Due to tumor heterogeneity, its efficacy greatly varies between patients and is limited due to adverse effects and drug resistance. Current in vitro models fail to recapitulate key features of HCCs. We report the generation of long-term organoid cultures from tumor needle ...[more]

PMID: 30067989

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Project description:In Rspondin-based three-dimensional cultures, Lgr5 stem cells from multiple organs form ever-expanding epithelial organoids that retain their tissue identity. Here we report the establishment of tumor organoid cultures from 20 consecutive colorectal carcinoma (CRC) patients. For most, organoids were also generated from adjacent normal tissue. Organoids closely resemble the original tumor. The spectrum of genetic changes within the 'living biobank' agrees well with previous large-scale mutational analyses of CRC. Gene expression analysis indicates that the major CRC molecular subtypes are represented. Tumor organoids are amenable to high-throughput drug screens allowing detection of gene-drug associations. As an example, a single organoid culture was exquisitely sensitive to Wnt secretion (porcupine) inhibitors and carried a mutation in the negative Wnt feedback regulator RNF43, rather than in APC. Organoid technology may fill the gap between cancer genetics and patient trials, complement cell line- and xenograft-based drug studies and allow personalized therapy design. Self-renewal of the intestinal epithelium is driven by Lgr5 stem cells located in crypts. We have recently developed a long-term culture system that maintains basic crypt physiology. Wnt signals are required for the maintenance of active crypt stem cells. Indeed, the Wnt agonist R-spondin1 induces dramatic crypt hyperplasia in vivo. R-spondin-1 is the ligand for Lgr5. Epidermal growth factor (EGF) signaling is associated with intestinal proliferation, while transgenic expression of Noggin induces a dramatic increase in crypt numbers. The combination of R-spondin-1, EGF, and Noggin in Matrigel sustains ever-expanding small intestinal organoids, which display all hallmarks of the original tissue in terms of architecture, cell type composition, and self-renewal dynamics. We adapted the culture condition for long-term expansion of human colonic epithelium and primary colonic adenocarcinoma, by adding nicotinamide, A83-01 (Alk inhibitor), Prostaglandin E2 and the p38 inhibitor SB202190. Of note, a two-dimensional culture method for cells from normal and malignant primary tissue has been described by Schlegel and colleagues. Here, we explore organoid technology to routinely establish and phenotypically annotate ‘paired organoids’ derived from adjacent tumor and healthy epithelium from CRC patients.

Dataset Information

Organoid Models of Human Liver Cancers Derived from Tumor Needle Biopsies

Publications

Organoid Models of Human Liver Cancers Derived from Tumor Needle Biopsies.

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