Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely owing to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent ...development of dense stroma are prominent features accounting for this aggressive biology
. The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumorigenesis and drug resistance
. Furthermore, PSC activation occurs very early during PDAC tumorigenesis
, and activated PSCs comprise a substantial fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an exploitable target to develop effective strategies for PDAC therapy and diagnosis. Here, starting with a systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukaemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion markedly slow tumour progression and augment the efficacy of chemotherapy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and epithelial-mesenchymal transition status. Moreover, in both mouse models and human PDAC, aberrant production of LIF in the pancreas is restricted to pathological conditions and correlates with PDAC pathogenesis, and changes in the levels of circulating LIF correlate well with tumour response to therapy. Collectively, these findings reveal a function of LIF in PDAC tumorigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. Our studies underscore how a better understanding of cell-cell communication within the tumour microenvironment can suggest novel strategies for cancer therapy.
While diet-induced obesity has been exclusively attributed to increased caloric intake from fat, animals fed a high-fat diet (HFD) ad libitum (ad lib) eat frequently throughout day and night, ...disrupting the normal feeding cycle. To test whether obesity and metabolic diseases result from HFD or disruption of metabolic cycles, we subjected mice to either ad lib or time-restricted feeding (tRF) of a HFD for 8 hr per day. Mice under tRF consume equivalent calories from HFD as those with ad lib access yet are protected against obesity, hyperinsulinemia, hepatic steatosis, and inflammation and have improved motor coordination. The tRF regimen improved CREB, mTOR, and AMPK pathway function and oscillations of the circadian clock and their target genes' expression. These changes in catabolic and anabolic pathways altered liver metabolome and improved nutrient utilization and energy expenditure. We demonstrate in mice that tRF regimen is a nonpharmacological strategy against obesity and associated diseases.
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► Time-restricted feeding improves clock and nutrient sensor functions ► tRF prevents obesity, diabetes, and liver diseases in mice on a high-fat diet ► Nutrient type and time of feeding determine liver metabolome and nutrient homeostasis ► tRF raises bile acid production and energy expenditure and reduces inflammation
Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of ...progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) proteins, abrogate cytokine-induced activation of HSCs. Cistromic analyses reveal that BRD4 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, where BRD4 is colocalized with profibrotic transcription factors. Furthermore, we show that JQ1 is not only protective, but can reverse the fibrotic response in carbon tetrachloride-induced fibrosis in mouse models. Our results implicate that BRD4 can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription. This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications.
Sickness-induced anorexia is a conserved behavior induced during infections. Here, we report that an intestinal pathogen, Salmonella Typhimurium, inhibits anorexia by manipulating the gut-brain axis. ...Inhibition of inflammasome activation by the S. Typhimurium effector, SlrP, prevented anorexia caused by IL-1β-mediated signaling to the hypothalamus via the vagus nerve. Rather than compromising host defenses, pathogen-mediated inhibition of anorexia increased host survival. SlrP-mediated inhibition of anorexia prevented invasion and systemic infection by wild-type S. Typhimurium, reducing virulence while increasing transmission to new hosts, suggesting that there are trade-offs between transmission and virulence. These results clarify the complex and contextual role of anorexia in host-pathogen interactions and suggest that microbes have evolved mechanisms to modulate sickness-induced behaviors to promote health of their host and their transmission at the expense of virulence.
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•Feeding status of host regulates pathogen virulence and transmission•Pathogen inhibition of IL-1β prevents anorexia via the gut-brain axis•Pathogen inhibition of anorexia promotes host survival and pathogen transmission•Sickness-induced anorexia creates trade-offs between virulence and transmission
Pathogens can interfere with the gut-brain circuits that control host anorexia during infection to promote host survival while facilitating disease transmission.
Age-associated insulin resistance (IR) and obesity-associated IR are two physiologically distinct forms of adult-onset diabetes. While macrophage-driven inflammation is a core driver of ...obesity-associated IR, the underlying mechanisms of the obesity-independent yet highly prevalent age-associated IR are largely unexplored. Here we show, using comparative adipo-immune profiling in mice, that fat-resident regulatory T cells, termed fTreg cells, accumulate in adipose tissue as a function of age, but not obesity. Supporting the existence of two distinct mechanisms underlying IR, mice deficient in fTreg cells are protected against age-associated IR, yet remain susceptible to obesity-associated IR and metabolic disease. By contrast, selective depletion of fTreg cells via anti-ST2 antibody treatment increases adipose tissue insulin sensitivity. These findings establish that distinct immune cell populations within adipose tissue underlie ageing- and obesity-associated IR, and implicate fTreg cells as adipo-immune drivers and potential therapeutic targets in the treatment of age-associated IR.
Pathogen virulence exists on a continuum. The strategies that drive symptomatic or asymptomatic infections remain largely unknown. We took advantage of the concept of lethal dose 50 (LD50) to ask ...which component of individual non-genetic variation between hosts defines whether they survive or succumb to infection. Using the enteric pathogen Citrobacter, we found no difference in pathogen burdens between healthy and symptomatic populations. Iron metabolism-related genes were induced in asymptomatic hosts compared to symptomatic or naive mice. Dietary iron conferred complete protection without influencing pathogen burdens, even at 1000× the lethal dose of Citrobacter. Dietary iron induced insulin resistance, increasing glucose levels in the intestine that were necessary and sufficient to suppress pathogen virulence. A short course of dietary iron drove the selection of attenuated Citrobacter strains that can transmit and asymptomatically colonize naive hosts, demonstrating that environmental factors and cooperative metabolic strategies can drive conversion of pathogens toward commensalism.
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•Lethal dose 50 can be used to identify cooperative defense mechanisms•Dietary iron promotes cooperative defenses against a lethal enteric infection•Insulin resistance reduces gut glucose absorption•Cooperative defenses drive selection for attenuated pathogen strains
Defense strategies that are cooperative rather than antagonistic can promote asymptomatic infection and select for reduced virulence in a bacterial pathogen.
The LKB1 (also called STK11) tumor suppressor is mutationally inactivated in ∼20% of non-small cell lung cancers (NSCLC). LKB1 is the major upstream kinase activating the energy-sensing kinase AMPK, ...making LKB1-deficient cells unable to appropriately sense metabolic stress. We tested the therapeutic potential of metabolic drugs in NSCLC and identified phenformin, a mitochondrial inhibitor and analog of the diabetes therapeutic metformin, as selectively inducing apoptosis in LKB1-deficient NSCLC cells. Therapeutic trials in Kras-dependent mouse models of NSCLC revealed that tumors with Kras and Lkb1 mutations, but not those with Kras and p53 mutations, showed selective response to phenformin as a single agent, resulting in prolonged survival. This study suggests phenformin as a cancer metabolism-based therapeutic to selectively target LKB1-deficient tumors.
► Phenformin is a mitochondrial inhibitor that selectively kills LKB1−/− NSCLC cells ► LKB1−/− NSCLC cells exhibit defective mitochondria and ROS following phenformin ► Phenformin improves tumors and survival in KrasG12DLkb1−/−, not KrasG12Dp53−/− mice ► eIF2α signaling markers are AMPK-independent biomarkers of biguanide treatment
Resuscitative endovascular balloon occlusion of the aorta (REBOA) causes a severe ischemia-reperfusion injury. Endovascular Perfusion Augmentation for Critical Care (EPACC) has emerged as a ...hemodynamic/mechanical adjunct to vasopressors and crystalloid for the treatment of post-REBOA ischemia-reperfusion injury. The objective of the study is to examine the impact of EPACC as a tool for a wean from complete REBOA compared to standard resuscitation techniques.
Nine swine underwent anesthesia and then a controlled 30% blood volume hemorrhage with 30 min of supraceliac total aortic occlusion to create an ischemia-reperfusion injury. Animals were randomized to standardized critical care (SCC) or 90 min of EPACC followed by SCC. The critical care phase lasted 270 min after injury. Hemodynamic markers and laboratory values of ischemia were recorded.
During the first 90 min the intervention phase SCC spent 60% (54%-73%) and EPACC spent 91% (88%-92%) of the time avoiding proximal hypotension (<60 mm Hg), P = 0.03. There was also a statistically significant decrease in cumulative norepinephrine dose at the end of the experiment between SCC (80.89 mcg/kg) versus EPACC (22.03 mcg/kg), P = 0.03. Renal artery flow during EPACC was similar compared to SCC during EPACC, P = 0.19. But during the last hour of the experiment (after removal of aortic balloon) the renal artery flow in EPACC (2.9 mL/kg/min) was statistically significantly increased compared to SCC (1.57 mL/min/kg), P = 0.03. There was a statistically significant decrease in terminal creatinine in the EPACC (1.7 mg/dL) compared to SCC (2.1 mg/dL), P = 0.03.
The 90 min of EPACC as a weaning adjunct in the setting of a severe ischemia-reperfusion injury after complete supraceliac REBOA provides improved renal flow with improvement in terminal creatinine compared to SCC with stabilized proximal hemodynamics and decreased vasopressor dose.
The sensation of pain is associated with increased mortality, but it is unknown whether pain perception can directly affect aging. We find that mice lacking TRPV1 pain receptors are long-lived, ...displaying a youthful metabolic profile at old age. Loss of TRPV1 inactivates a calcium-signaling cascade that ends in the nuclear exclusion of the CREB-regulated transcriptional coactivator CRTC1 within pain sensory neurons originating from the spinal cord. In long-lived TRPV1 knockout mice, CRTC1 nuclear exclusion decreases production of the neuropeptide CGRP from sensory endings innervating the pancreatic islets, subsequently promoting insulin secretion and metabolic health. In contrast, CGRP homeostasis is disrupted with age in wild-type mice, resulting in metabolic decline. We show that pharmacologic inactivation of CGRP receptors in old wild-type animals can restore metabolic health. These data suggest that ablation of select pain sensory receptors or the inhibition of CGRP are associated with increased metabolic health and control longevity.
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•Mutation of TRPV1 extends lifespan in mice and worms via CRTC1/CREB signaling•TRPV1 mutant mice have normal growth but have a youthful metabolism late in life•TRPV1 impact on metabolism through secretion of CGRP, an insulin secretion blocker•Chemical inhibition of CGRP increases metabolic health at old age
The ablation of select pain sensory receptors is associated with increased metabolic health and longevity.
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