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1.
Nature ; 593(7858): 282-288, 2021 05.
Article in English | MEDLINE | ID: mdl-33828302

ABSTRACT

Cancer cells characteristically consume glucose through Warburg metabolism1, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells2-4. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.


Subject(s)
Neoplasms/metabolism , Neoplasms/pathology , Nutrients/metabolism , Tumor Microenvironment , Animals , Carcinoma, Renal Cell/immunology , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Cell Line, Tumor , Female , Glucose/metabolism , Glutamine/metabolism , Humans , Lipid Metabolism , Male , Mechanistic Target of Rapamycin Complex 1/metabolism , Mice , Myeloid Cells/immunology , Myeloid Cells/metabolism , Neoplasms/immunology , Tumor Microenvironment/immunology
2.
JCI Insight ; 5(10)2020 05 21.
Article in English | MEDLINE | ID: mdl-32369448

ABSTRACT

The Wnt/ß-catenin signaling pathway plays an important role in renal development and is reexpressed in the injured kidney and other organs. ß-Catenin signaling is protective in acute kidney injury (AKI) through actions on the proximal tubule, but the current dogma is that Wnt/ß-catenin signaling promotes fibrosis and development of chronic kidney disease (CKD). As the role of proximal tubular ß-catenin signaling in CKD remains unclear, we genetically stabilized (i.e., activated) ß-catenin specifically in murine proximal tubules. Mice with increased tubular ß-catenin signaling were protected in 2 murine models of AKI to CKD progression. Oxidative stress, a common feature of CKD, reduced the conventional T cell factor/lymphoid enhancer factor-dependent ß-catenin signaling and augmented FoxO3-dependent activity in proximal tubule cells in vitro and in vivo. The protective effect of proximal tubular ß-catenin in renal injury required the presence of FoxO3 in vivo. Furthermore, we identified cystathionine γ-lyase as a potentially novel transcriptional target of ß-catenin/FoxO3 interactions in the proximal tubule. Thus, our studies overturned the conventional dogma about ß-catenin signaling and CKD by showing a protective effect of proximal tubule ß-catenin in CKD and identified a potentially new transcriptional target of ß-catenin/FoxO3 signaling that has therapeutic potential for CKD.


Subject(s)
Forkhead Box Protein O3/metabolism , Kidney Tubules, Proximal/metabolism , Renal Insufficiency, Chronic/metabolism , Signal Transduction , beta Catenin/metabolism , Acute Kidney Injury/genetics , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Animals , Forkhead Box Protein O3/genetics , Kidney Tubules, Proximal/pathology , Male , Mice , Mice, Transgenic , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/pathology , beta Catenin/genetics
3.
Arterioscler Thromb Vasc Biol ; 40(6): e153-e165, 2020 06.
Article in English | MEDLINE | ID: mdl-32295422

ABSTRACT

OBJECTIVE: Macrophages have been described in calcific aortic valve disease, but it is unclear if they promote or counteract calcification. We aimed to determine how macrophages are involved in calcification using the Notch1+/- model of calcific aortic valve disease. Approach and Results: Macrophages in wild-type and Notch1+/- murine aortic valves were characterized by flow cytometry. Macrophages in Notch1+/- aortic valves had increased expression of MHCII (major histocompatibility complex II). We then used bone marrow transplants to test if differences in Notch1+/- macrophages drive disease. Notch1+/- mice had increased valve thickness, macrophage infiltration, and proinflammatory macrophage maturation regardless of transplanted bone marrow genotype. In vitro approaches confirm that Notch1+/- aortic valve cells promote macrophage invasion as quantified by migration index and proinflammatory phenotypes as quantified by Ly6C and CCR2 positivity independent of macrophage genotype. Finally, we found that macrophage interaction with aortic valve cells promotes osteogenic, but not dystrophic, calcification and decreases abundance of the STAT3ß isoform. CONCLUSIONS: This study reveals that Notch1+/- aortic valve disease involves increased macrophage recruitment and maturation driven by altered aortic valve cell secretion, and that increased macrophage recruitment promotes osteogenic calcification and alters STAT3 splicing. Further investigation of STAT3 and macrophage-driven inflammation as therapeutic targets in calcific aortic valve disease is warranted.


Subject(s)
Aortic Valve Stenosis/pathology , Aortic Valve/pathology , Calcinosis/pathology , Macrophages/physiology , STAT3 Transcription Factor/physiology , Animals , Aortic Valve/immunology , Aortic Valve/physiopathology , Aortic Valve Stenosis/immunology , Aortic Valve Stenosis/physiopathology , Bone Marrow Transplantation , Calcinosis/immunology , Calcinosis/physiopathology , Cell Movement , Cyclic S-Oxides/pharmacology , Disease Models, Animal , Gene Expression , Genotype , Humans , Inflammation/pathology , Macrophages/chemistry , Macrophages/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Osteogenesis , Receptor, Notch1/analysis , Receptor, Notch1/genetics , Receptor, Notch1/physiology , STAT3 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/genetics
4.
Semin Nephrol ; 40(2): 126-137, 2020 03.
Article in English | MEDLINE | ID: mdl-32303276

ABSTRACT

Acute kidney injury (AKI) portends a poor clinical prognosis and increases the risk for the development of chronic kidney disease (CKD). Currently, there are no therapies to treat AKI or prevent its progression to CKD. Wnt/ß-catenin is a critical regulator of kidney development that is up-regulated after injury. Most of the literature support a beneficial role for Wnt/ß-catenin in AKI, but suggest that this pathway promotes the progression of tubulointerstitial fibrosis, the hallmark of CKD progression. We review the role of Wnt/ß-catenin in renal injury with a focus on its potential as a therapeutic target in AKI and in AKI to CKD transition.


Subject(s)
Acute Kidney Injury/metabolism , Kidney Tubules/metabolism , Renal Insufficiency, Chronic/metabolism , Wnt Signaling Pathway/physiology , Acute Kidney Injury/physiopathology , Animals , Disease Progression , Fibrosis , Humans , Kidney/pathology , Kidney Tubules/pathology , Kidney Tubules/physiopathology , Renal Insufficiency, Chronic/physiopathology
5.
Nat Biomed Eng ; 4(4): 407-420, 2020 04.
Article in English | MEDLINE | ID: mdl-31988458

ABSTRACT

Organ chips can recapitulate organ-level (patho)physiology, yet pharmacokinetic and pharmacodynamic analyses require multi-organ systems linked by vascular perfusion. Here, we describe an 'interrogator' that employs liquid-handling robotics, custom software and an integrated mobile microscope for the automated culture, perfusion, medium addition, fluidic linking, sample collection and in situ microscopy imaging of up to ten organ chips inside a standard tissue-culture incubator. The robotic interrogator maintained the viability and organ-specific functions of eight vascularized, two-channel organ chips (intestine, liver, kidney, heart, lung, skin, blood-brain barrier and brain) for 3 weeks in culture when intermittently fluidically coupled via a common blood substitute through their reservoirs of medium and endothelium-lined vascular channels. We used the robotic interrogator and a physiological multicompartmental reduced-order model of the experimental system to quantitatively predict the distribution of an inulin tracer perfused through the multi-organ human-body-on-chips. The automated culture system enables the imaging of cells in the organ chips and the repeated sampling of both the vascular and interstitial compartments without compromising fluidic coupling.


Subject(s)
Cell Culture Techniques/methods , Lab-On-A-Chip Devices , Microfluidics/methods , Robotics/methods , Blood-Brain Barrier , Brain , Calibration , Cell Culture Techniques/instrumentation , Equipment Design , Heart , Humans , Intestines , Kidney , Liver , Lung , Robotics/instrumentation , Skin
6.
Nat Biomed Eng ; 4(4): 421-436, 2020 04.
Article in English | MEDLINE | ID: mdl-31988459

ABSTRACT

Analyses of drug pharmacokinetics (PKs) and pharmacodynamics (PDs) performed in animals are often not predictive of drug PKs and PDs in humans, and in vitro PK and PD modelling does not provide quantitative PK parameters. Here, we show that physiological PK modelling of first-pass drug absorption, metabolism and excretion in humans-using computationally scaled data from multiple fluidically linked two-channel organ chips-predicts PK parameters for orally administered nicotine (using gut, liver and kidney chips) and for intravenously injected cisplatin (using coupled bone marrow, liver and kidney chips). The chips are linked through sequential robotic liquid transfers of a common blood substitute by their endothelium-lined channels (as reported by Novak et al. in an associated Article) and share an arteriovenous fluid-mixing reservoir. We also show that predictions of cisplatin PDs match previously reported patient data. The quantitative in-vitro-to-in-vivo translation of PK and PD parameters and the prediction of drug absorption, distribution, metabolism, excretion and toxicity through fluidically coupled organ chips may improve the design of drug-administration regimens for phase-I clinical trials.


Subject(s)
Lab-On-A-Chip Devices , Microfluidics/methods , Pharmaceutical Preparations , Pharmacokinetics , Animals , Cisplatin/pharmacokinetics , Drug Design , Humans , In Vitro Techniques , Liver/metabolism , Microfluidics/instrumentation , Models, Biological , Nicotine/pharmacokinetics , Pharmaceutical Preparations/administration & dosage , Pharmaceutical Preparations/metabolism
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