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Hepatocyte thorns, a novel drug-induced stress response in human and mouse liver spheroids

ABSTRACT: The in vivo-relevant phenotype of 3D liver spheroids allows for long-term studies of e.g. novel mechanisms of chronic drug-induced liver toxicity. Using this system, we present a novel drug-induced stress response in human and murine hepatocyte spheroids wherein long slender filaments form after chronic treatment with four different drugs, of which, three are PPARα an-tagonists. The morphology of the thorns varies between donors and compounds used. They are mainly composed of diverse protein fibres, which are glycosylated. Their formation is inhibited by treatment with fatty acids or antioxidants. Treatment of mice with GW6471, revealed changes in gene and protein expression like those in the spheroids. In addition, similar changes in kera-tin expression were seen following treatment of hepatotoxic drugs including aflatoxin B1, para-cetamol, chlorpromazine, cyclosporine and ketoconazole. We suggest that thorn formation may be indicative of hepatocyte metaplasia in response to toxicity and that more focus should be placed on alterations of ECM derived protein expression as biomarkers of liver disease and chronic drug-induced hepatotoxicity, changes that can be studied in stable in vivo-like hepatic cell systems like the spheroids.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Liver

SUBMITTER: Massimiliano Gaetani

LAB HEAD: Massimiliano Gaetani

PROVIDER: PXD033550 | Pride | 2022-05-26

REPOSITORIES: Pride

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Project description:Summary: Melanoma spheroids grown under neural crest cell conditions are highly plastic migratory/invasive tumor cells endowed with immunomodulator function Background: The aggressiveness of melanoma tumors is likely to rely on their well-recognized heterogeneity and plasticity. Melanoma comprises multi subpopulations of cancer cells some of which may possess stem cell-like properties supporting the notion of plasticity. Although useful for certain tumors, the use of the sphere-formation assay to identify stem cell-like or tumor initiating cells subpopulations in human melanoma has been recently challenged. Our study reveals that this assay predicts a functional phenotype associated with aggressive behavior of tumor cells. Methodology/Principal Findings: We analyzed the molecular and functional phenotypes of melanoma spheroids formed in neural crest cell medium. Whether from metastatic (SLM8) or advanced primary (Mela1) tumors, spheroid cells expressed melanoma-associated markers. They displayed higher capacity to differentiate along mesenchymal lineages, and showed enhanced expression of SOX2, NANOG, KLF4, and/or OCT4 transcription factors, but not extensive self-renewal or enhanced tumorigenicity when compared to their adherent counterparts. To determine whether melanoma spheroids in our model could predict a molecular or functional phenotype, we performed gene expression profiling experiments using Affymetrix microarrays. Gene expression profiling attributed a neural crest cell signature to these spheroids and indicated that a migratory/invasive and immune-function modulating program could be associated with these cells. In vitro assays confirmed that these spheroids are endowed with enhanced migratory/invasive capacities. In immune activation assays, spheroid cells elicited a poorer allogenic response from immune cells and inhibited mitogen-dependent T cells activation and proliferation more efficiently than their adherent counterparts. Thus, our findings reveal novel immune-modulator function of melanoma spheroid cells and suggest specific roles for these spheroids in invasion and in evasion of antitumor immunity. Conclusion/Significance: The association of a more plastic, invasive and evasive, thus a more aggressive tumor phenotype with melanoma spheroid cells reveals a previously unrecognized aspect of tumor cells expanded as spheroid cultures. While of limited efficiency for melanoma initiating cell identification, our melanoma spheroid model predicted aggressive phenotype and could therefore, be constructive to investigate melanoma aggressiveness, relevant to patients and clinical transferability. 12 Total samples were analyzed: SLM8 adherent (SLMA) and spheroids (SLMS) cells, and Mela1 adherent (MelaA) and spheroid (MelaS) cells, all performed in triplicates. Paired statistical analyses were performed using Student's paired t-test on the gene signal intensities (gene level) and results were considered statistically significant at p-values <=0.05 and fold-change >=1.5.

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Hepatocyte thorns, a novel drug-induced stress response in human and mouse liver spheroids

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