In this issue, Wang et al. report a human cellular model of Bardet-Biedl Syndrome (BBS), a ciliopathy characterized by hyperphagic obesity, using patient-specific induced pluripotent stem cell–derived (iPSC-derived) hypothalamic arcuate-like neurons. Their findings indicate that BBS proteins impact energy homeostasis by regulating cilia length and neuronal morphology, and by controlling key intracellular signaling pathways, such as insulin and leptin signaling. The cover image shows iPSC-derived neurons with a mutation in BBS10A stained for the neuronal markers TUJ1 (red) and MAP2 (green), with overlapping regions shown in yellow and Draq5-stained nuclei (blue).
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Rapidly growing tumors often experience hypoxia and nutrient (e.g., glucose) deficiency because of poor vascularization. Tumor cells respond to the cytotoxic effects of such stresses by inducing molecular adaptations that promote clonal selection of a more malignant tumor-initiating cell phenotype, especially in the innermost tumor regions. Here, we report a regulatory mechanism involving fucosylation by which glucose restriction promotes cancer stemness to drive drug resistance and tumor recurrence. Using hepatocellular carcinoma (HCC) as a model, we showed that restricted glucose availability enhanced the PERK-eIF2α-ATF4 signaling axis to drive fucosyltransferase-1 (FUT1) transcription via direct binding of ATF4 to the FUT1 promoter. FUT1 overexpression is a poor prognostic indicator for HCC. FUT1 inhibition could mitigate tumor initiation, self-renewal and drug resistance. Mechanistically, we demonstrated that CD147, ICAM-1, EGFR and EPHA2 are glycoprotein targets of FUT1, where such fucosylation would consequently converge on deregulated AKT-mTOR-4EBP1 signaling to drive cancer stemness. Treatment with an α-(1,2)-fucosylation inhibitor sensitized HCC tumors to sorafenib, a first-line molecular targeted drug used for advanced HCC patients, and reduced the tumor-initiating subset. FUT1 overexpression and/or CD147, ICAM-1, EGFR and EPHA2 fucosylation may be good prognostic markers and therapeutic targets for cancer patients.
Jane H.C. Loong, Tin-Lok Wong, Man Tong, Rakesh Sharma, Lei Zhou, Kai-Yu Ng, Hua-Jian Yu, Chi Han Li, Kwan Man, Chung-Mau Lo, Xin-Yuan Guan, Terence K. Lee, Jing-Ping Yun, Stephanie Kwai Yee Ma
The ability to adapt to low-nutrient microenvironments is essential for tumor-cell survival and progression in solid cancers, such as colorectal carcinoma (CRC). Signaling by the NF-κB transcription-factor pathway associates with advanced disease stages and shorter survival in CRC patients. NF-κB has been shown to drive tumor-promoting inflammation, cancer-cell survival and intestinal epithelial cell (IEC) dedifferentiation in mouse models of CRC. However, whether NF-κB affects the metabolic adaptations that fuel aggressive disease in CRC patients is unknown. Here, we identified carboxylesterase 1 (CES1) as an essential NF-κB-regulated lipase linking obesity-associated inflammation with fat metabolism and adaptation to energy stress in aggressive CRC. CES1 promoted CRC-cell survival via cell-autonomous mechanisms that fuel fatty-acid oxidation (FAO) and prevent the toxic build-up of triacylglycerols. We found that elevated CES1 expression correlated with worse outcomes in overweight CRC patients. Accordingly, NF-κB drove CES1 expression in CRC consensus molecular subtype (CMS)4, associated with obesity, stemness and inflammation. CES1 was also upregulated by gene amplifications of its transcriptional regulator, HNF4A, in CMS2 tumors, reinforcing its clinical relevance as a driver of CRC. This subtype-based distribution and unfavourable prognostic correlation distinguished CES1 from other intracellular triacylglycerol lipases and suggest CES1 could provide a route to treat aggressive CRC.
Daria Capece, Daniel D'Andrea, Federica Begalli, Laura Goracci, Laura Tornatore, James L. Alexander, Alessandra Di Veroli, Shi-Chi Leow, Thamil S. Vaiyapuri, James K. Ellis, Daniela Verzella, Jason Bennett, Luca Savino, Yue Ma, James S. McKenzie, Maria Luisa Doria, Sam E. Mason, Kern Rei Chng, Hector C. Keun, Gary Frost, Vinay Tergaonkar, Katarzyna Broniowska, Walter Stunkel, Zoltan Takats, James M. Kinross, Gabriele Cruciani, Guido Franzoso
Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by recessive, loss-of-function mutations in FIG4, encoding a phosphoinositol(3,5)P2-phosphatase. CMT4J patients have both neuron loss and demyelination in the peripheral nervous system, with vacuolization indicative of endosome/lysosome trafficking defects. Although the disease is highly variable, the onset is often in childhood and FIG4 mutations can dramatically shorten lifespan. There is currently no treatment for CMT4J. Here we present the results of preclinical studies testing a gene therapy approach to restore FIG4 expression. A mouse model of CMT4J, the Fig4-pale tremor (plt) allele, was dosed with a single-stranded AAV9 to deliver a codon-optimized human FIG4 sequence. Untreated, Fig4plt/plt mice have a median survival of approximately 5 weeks. When treated with the AAV9-FIG4 vector at postnatal day 1 or 4, mice survived at least one year, with largely normal gross motor performance and little sign of neuropathy by neurophysiological or histopathological evaluation. When treated at postnatal day 7 or 11, life span was still significantly prolonged and peripheral nerve function was improved, but rescue was less complete. No unanticipated adverse effects were observed. Therefore, AAV9-mediated delivery of FIG4 is a well-tolerated and efficacious strategy in a mouse model of CMT4J.
Maximiliano Presa, Rachel M. Bailey, Crystal Davis, Tara Murphy, Jenn Cook, Randy Walls, Hannah Wilpan, Laurent Bogdanik, Guy M. Lenk, Robert W. Burgess, Steven J. Gray, Cathleen Lutz
Dysregulated protein degradative pathways are increasingly recognized as mediators of human disease. This mechanism may have particular relevance to desmosomal proteins that play critical structural roles in both tissue architecture and cell-cell communication as destabilization/breakdown of the desmosomal proteome is a hallmark of genetic-based desmosomal-targeted diseases, such as the cardiac disease, arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, no information exists on whether there are resident proteins that regulate desmosomal proteome homeostasis. Here we uncovered a cardiac COP9 desmosomal resident protein complex, composed of subunit 6 of the COP9 signalosome (CSN6), that enzymatically restricted neddylation and targeted desmosomal proteome degradation. CSN6 binding, localization, levels and function were impacted in hearts of classic mouse and human models of ARVD/C impacted by desmosomal loss and mutations, respectively. Loss of desmosomal proteome degradation control due to CSN6 loss and human desmosomal mutations destabilizing CSN6 were also sufficient to trigger ARVD/C in mice. We identified a desmosomal resident regulatory complex that restricted desmosomal proteome degradation and disease.
Yan Liang, Robert C. Lyon, Jason Pellman, William H. Bradford, Stephan Lange, Julius Bogomolovas, Nancy D. Dalton, Yusu Gu, Marcus Bobar, Mong-Hong Lee, Tomoo Iwakuma, Vishal Nigam, Angeliki Asimaki, Melvin Scheinman, Kirk L. Peterson, Farah Sheikh
Synaptic plasticity is identified as innate to hypothalamic feeding circuits in their adaptation to the changing metabolic milieu in control of feeding and obesity. However, less is known about the regulatory principles of the dynamic changes of AgRP perikarya, a crucial region of the neuron gating excitation, and hence, feeding. Here we show that AgRP neurons activated either by food deprivation, ghrelin or chemogenetics decreased their own inhibitory tone while triggering mitochondrial adaptations in neighboring astrocytes. We found that it was the inhibitory neurotransmitter, GABA, released by AgRP neurons that evoked this astrocytic response, which in turn, resulted in increased glial ensheetment of AgRP perikaryal by glial processes and increased excitability of AgRP neurons. We also identified that astrocyte-derived prostaglandin E2 directly activated, via EP2 receptors, AgRP neurons. Taken together, these observations unmasked a feedforward, self-exciting loop in AgRP neuronal control mediated by astrocytes, a mechanism directly relevant for hunger, feeding and overfeeding.
Luis Varela, Bernardo Stutz, Jae Eun Song, Jae Geun Kim, Zhong-Wu Liu, Xiao-Bing Gao, Tamas L. Horvath
JCI This Month is a digest of the research, reviews, and other features published each month.
Cancer cells in a solid tumor are supported by vasculature, extracellular matrix, nerves, and an immunological milieu collectively known as the tumor microenvironment. Elements within the tumor microenvironment can act in a coordinated fashion to support tumor growth, immune evasion, and metastasis. In this series, reviews curated by Series Editor Andrew Ewald highlight the tumor microenvironment’s complex effects in cancer, describing its modulation of immune cells and the tumor stroma as well as its role in disseminating metastases.