Loss of LKB1 is associated with increased metastasis and poor prognosis in lung cancer, but the development of targeted agents is in its infancy. Here we report that a glutaminolytic enzyme, glutamate dehydrogenase 1 (GDH1), upregulated upon detachment via pleomorphic adenoma gene 1 (PLAG1), provides anti-anoikis and pro-metastatic signals in LKB1-deficient lung cancer. Mechanistically, the GDH1 product α-KG activates CamKK2 by enhancing its substrate AMPK binding, which contributes to energy production that confers anoikis resistance. The effect of GDH1 on AMPK is evident in LKB1-deficient lung cancer, where AMPK activation predominantly depends on CamKK2. Targeting GDH1 with R162 attenuated tumor metastasis in patient-derived xenograft model and correlation studies in lung cancer patients further validated the clinical relevance of our finding. Our study provides insight into the molecular mechanism by which GDH1-mediated metabolic reprogramming of glutaminolysis mediates lung cancer metastasis and offers a therapeutic strategy for patients with LKB1-deficient lung cancer.
Highlights d HCC cells utilize NaCT-mediated citrate uptake for lipogenesis d Citrate import supports lipogenesis and anaplerosis upon glutamine deprivation d NaCT-mediated citrate uptake facilitates protection against zinc toxicity
Background: Stable isotope tracing has become an invaluable tool for probing the metabolism of biological systems. However, data analysis and visualization from metabolic tracing studies often involve multiple software packages and lack pathway architecture. A deep understanding of the metabolic contexts from such datasets is required for biological interpretation. Currently, there is no single software package that allows researchers to analyze and integrate stable isotope tracing data into annotated or custom-built metabolic networks. Results: We built a standalone web-based software, Escher-Trace, for analyzing tracing data and communicating results. Escher-Trace allows users to upload baseline corrected mass spectrometer (MS) tracing data and correct for natural isotope abundance, generate publication quality graphs of metabolite labeling, and present data in the context of annotated metabolic pathways. Here we provide a detailed walk-through of how to incorporate and visualize 13 C metabolic tracing data into the Escher-Trace platform. Conclusions: Escher-Trace is an open-source software for analysis and interpretation of stable isotope tracing data and is available at https://escher-trace.github.io/.
Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses and spreads by metastasis to the liver1. Cancer-associated fibroblasts, the extracellular matrix and type I collagen (Col I) support2,3 or restrain the progression of PDAC and may impede blood supply and nutrient availability4. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers to escape nutrient limitation, remain poorly understood. Here we show that matrix-metalloprotease-cleaved Col I (cCol I) and intact Col I (iCol I) exert opposing effects on PDAC bioenergetics, macropinocytosis, tumour growth and metastasis. Whereas cCol I activates discoidin domain receptor 1 (DDR1)–NF-κB–p62–NRF2 signalling to promote the growth of PDAC, iCol I triggers the degradation of DDR1 and restrains the growth of PDAC. Patients whose tumours are enriched for iCol I and express low levels of DDR1 and NRF2 have improved median survival compared to those whose tumours have high levels of cCol I, DDR1 and NRF2. Inhibition of the DDR1-stimulated expression of NF-κB or mitochondrial biogenesis blocks tumorigenesis in wild-type mice, but not in mice that express MMP-resistant Col I. The diverse effects of the tumour stroma on the growth and metastasis of PDAC and on the survival of patients are mediated through the Col I–DDR1–NF-κB–NRF2 mitochondrial biogenesis pathway, and targeting components of this pathway could provide therapeutic opportunities.
Purpose: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase (SDH) subunits (A–D) comprising less than 7.5% (i.e., 150–200/year) of new cases annually in the United States. Contrary to GISTs harboring KIT or PDGFRA mutations, SDH-mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKI). Lack of human models for any SDH-mutant tumors, including GIST, has limited molecular characterization and drug discovery. Experimental Design: We describe methods for establishing novel patient-derived SDH-mutant (mSDH) GIST models and interrogated the efficacy of temozolomide on these tumor models in vitro and in clinical trials of patients with mSDH GIST. Results: Molecular and metabolic characterization of our patient-derived mSDH GIST models revealed that these models recapitulate the transcriptional and metabolic hallmarks of parent tumors and SDH deficiency. We further demonstrate that temozolomide elicits DNA damage and apoptosis in our mSDH GIST models. Translating our in vitro discovery to the clinic, a cohort of patients with SDH-mutant GIST treated with temozolomide (n = 5) demonstrated a 40% objective response rate and 100% disease control rate, suggesting that temozolomide represents a promising therapy for this subset of GIST. Conclusions: We report the first methods to establish patient-derived mSDH tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in patients with mSDH GIST who are refractory to existing chemotherapeutic drugs (namely, TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic. See related commentary by Blakely et al., p. 3
BackgroundChronic obstructive pulmonary disease (COPD) is now recognized as a systemic disorder with many comorbidities. Atopy in patients with COPD and upper airways symptoms has not been characterized.ObjectiveWe investigated the occurrence and impact of aeroallergen sensitisation in patients with COPD and upper airways symptoms.MethodsAll 41 subjects with COPD diagnosed as per Global Initiative for Chronic Obstructive Lung Disease guidelines, underwent spirometry with reversibility, computed tomography of the paranasal sinuses (CT-PNS), skin prick test (SPT) against common aeroallergens and responded to St. George's Respiratory Questionnaire (SGRQ) and Sino Nasal Outcome Test - 22 (SNOT-22) questionnaires. Upper airways symptoms were assessed as per the Allergic Rhinitis and its Impact on Asthma guidelines.ResultsAs documented earlier, 27 of the 41 patients (65.9%) with COPD had upper airways symptoms. Of these 27 patients, 11 had SPT positivity against at least one aeroallergen (group 1). One patient had monosensitisation to pollens of grass Imperata while polysensitisation was seen in 10/11 patients commonly to weeds, trees, and insects. Fungal sensitisation to Aspergillus fumigatus was seen in 3 of 11 patients (27.2%). In group 1, all 11 patients (100%) had radiological sinusitis as compared to 8 of 16 (50%) in group 2. The mean CT-PNS scores were significantly higher in group 1 as compared to group 2. Similarly, the SNOT-22 scores were significantly higher in group 1 as compared to group 2. However, there was no difference in SGRQ scores between the 2 groups. In group 1, there was a significant correlation between CT-PNS and SNOT-22 scores.ConclusionPatients with COPD, associated upper airways symptoms and a positive SPT had a significantly higher frequency of radiological sinusitis on CT-PNS. They even had worse quality of life as compared to those with a negative SPT. The study suggested that atopic patients with COPD and upper airways involvement were more symptomatic. It is therefore possible that upper airways symptoms, if left untreated, would result in less than desirable control of the disease.
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