Retrodifferentiation of Human Tumor Hepatocytes to Stem Cells Leads to Metabolic Reprogramming and Chemoresistance

Abstract

Human hepatocellular carcinoma (HCC) heterogeneity promotes recurrence and therapeutic resistance. We recently demonstrated that inflammation favors hepatocyte retrodifferentiation into progenitor cells. Here, we identify the molecular effectors that induce metabolic reprogramming, chemoresistance, and invasiveness of retrodifferentiated HCC stem cells. Spheroid cultures of human HepaRG progenitors (HepaRG-Spheres), HBG-BC2, HepG2, and HuH7 cells and isolation of side population (SP) from HepaRG cells (HepaRG-SP) were analyzed by transcriptomics, signaling pathway analysis, and evaluation of chemotherapies. Gene expression profiling of HepaRG-SP and HepaRG-Spheres revealed enriched signatures related to cancer stem cells, metastasis, and recurrence and showed that HepaRG progenitors could retrodifferentiate into an immature state. The transcriptome from these stem cells matched that of proliferative bad outcome HCCs in a cohort of 457 patients. These HCC stem cells expressed high levels of cytokines triggering retrodifferentiation and displayed high migration and invasion potential. They also showed changes in mitochondrial activity with reduced membrane potential, low ATP production, and high lactate production. These changes were, in part, related to angiopoietin-like 4 (ANGPTL4)induced upregulation of pyruvate dehydrogenase kinase 4 (PDK4), an inhibitor of mitochondrial pyruvate dehydrogenase. Upregulation of ANGPTL4 and PDK4 paralleled that of stem cells markers in human HCC specimens. Moreover, the PDK4 inhibitor dichloroacetate reversed chemoresistance to sorafenib or cisplatin in HCC stem cells derived from four HCC cell lines. In conclusion, retrodifferentiated cancer cells develop enhanced invasion and therapeutic resistance through ANGPTL4 and PDK4. Therefore, restoration of mitochondrial activity in combination with chemotherapy represents an attractive therapeutic approach in HCC. Significance: Restoring mitochondrial function in human hepatocellular carcinomas overcomes cancer resistance.

Mapping a Circular RNA–microRNA–mRNA-Signaling Regulatory Axis that Modulates Stemness Properties of Cancer Stem Cell Populations in Colorectal Cancer Spheroid Cells

“…In line with other works [49,50], the spheroidal culture showed passage-dependent phenotypic and molecular changes and displayed multiple features of stemness properties tested, including up-regulated expression of pluripotency factors, enhanced self-renewal, cell migration and invasion abilities, and multi-lineage differentiation (Figures 1 and 2). Chemoresistance to 5-FU and oxaliplatin was enhanced in increasing passages of the spheroid cells, further supporting CSC enrichment in the spheroids (Figure 2F,G), as has also been reported for CRC and other cancers [51][52][53]. The ability of the cells to differentiate into ectodermic and mesodermic lineages supported the pluripotency of the CSC in the spheroids, as was also reported for CRC cancer stem cell-like population to differentiate into mucin-producing goblet cells, enterocyte-like and neuroendocrine-like cells [18].…”

Meningitic Escherichia coli Induction of ANGPTL4 in Brain Microvascular Endothelial Cells Contributes to Blood–Brain Barrier Disruption via ARHGAP5/RhoA/MYL5 Signaling Cascade

“…A study showed that nANGPTL4 is an orphan ligand that mainly controls lipid metabolism and cANGPTL4 binds-e.g., β-integrins, VE-cadherin, and claudin-5-to induce vascular leakage and tumor progression [19]. An increasing number of studies have indicated the possible involvement of ANGPTL4 in the development of cardiovascular diseases [20][21][22], inflammatory diseases [23][24][25][26], cancers [27][28][29], etc. However, there are still no reports on the role of ANGPTL4 in bacterial meningitis.…”

Inhibiting CBX4 efficiently suppress YAP nucleus translocation in hepatocellular carcinoma cells to protect against sorafenib resistance

“…However, SR HCC is causally linked to the maintenance of stem-like properties [27]. Enriched spheres with SR signatures have been related to CSCs, metastasis, and recurrence of HCC [28]. These findings provide us with confidence in defining the correlation between expression significantly inhibited SR cells by reducing apoptosis through the AKT/ERK pathway [31] and tumor-initiating cell phenotypes [32].…”