Reciprocal links between methionine metabolism, DNA repair and therapy resistance in glioblastoma.

Glioblastoma (GBM) is uniformly lethal due to profound treatment resistance. Altered cellular metabolism is a key mediator of GBM treatment resistance. Uptake of the essential sulfur-containing amino acid methionine is drastically elevated in GBMs compared to normal cells, however, it is not known how this methionine is utilized or whether it relates to GBM treatment resistance.

Ascitic Shear Stress Activates GPCRs and Downregulates Mucin 15 to Promote OvarianCancer Malignancy.

The accumulation of ascites in patients with ovarian cancer increases their risk of transcoelomic metastasis. Although common routes of peritoneal dissemination are known to follow distinct paths of circulating ascites, the mechanisms that initiate these currents and subsequent fluid shear stresses are not well understood. Here, we developed a patient-based, boundary-driven computational fluid dynamics model to predict an upper range of fluid shear stress generated by the accumulation of ascites.

Inulin-gel-based oral immunotherapy remodels the small intestinal microbiome and suppresses food allergy.

Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models.

Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication.

Viruses are obligate intracellular parasites that rely on host cell metabolism for successful replication. Thus, viruses rewire host cell pathways involved in central carbon metabolism to increase the availability of building blocks for successful propagation. However, the underlying mechanisms of virus-induced alterations to host metabolism are largely unknown.

Comprehensive sampling of the lung microbiome in early-stage non-small cell lung cancer.

Objectives: Data are scarce on whether the composition of the lung microbiome (extending from the nasopharynx to the peripheral lung tissue) varies according to histology or grade of non-small cell lung cancer. We hypothesized that the composition of the lung microbiome would vary according to the histology and the grade of non-small cell lung cancer.

Methods: We collected naso-oral and central lobar (cancer affected, ipsilateral unaffected, and contralateral unaffected) bronchoalveolar lavage fluid and brushing samples from patients with clinical early-stage lung cancer between July 2018 and February 2020 at a single academic center.

Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication.

Viruses are obligate intracellular parasites that rely on host cell metabolism for successful replication. Thus, viruses rewire host cell pathways involved in central carbon metabolism to increase the availability of building blocks for replication. However, the underlying mechanisms of virus-induced alterations to host metabolism are largely unknown.

Devimistat in Combination with Gemcitabine and Cisplatin in Biliary Tract Cancer: Preclinical Evaluation and Phase Ib Multicenter Clinical Trial (BilT-04).

Purpose: Devimistat (CPI-613) is a novel inhibitor of tumoral mitochondrial metabolism. We investigated the effect of devimistat in vitro and in a phase Ib clinical trial in patients with advanced biliary tract cancer (BTC).

Patients And Methods: Cell viability assays of devimistat ± gemcitabine and cisplatin (GC) were performed and the effect of devimistat on mitochondrial respiration via oxygen consumption rate (OCR) was evaluated.

Exploiting metabolic vulnerabilities after anti-VEGF antibody therapy in ovarian cancer.

Despite modest clinical improvement with anti-vascular endothelial growth factor antibody (AVA) therapy in ovarian cancer, adaptive resistance is ubiquitous and additional options are limited. A dependence on glutamine metabolism, via the enzyme glutaminase (GLS), is a known mechanism of adaptive resistance and we aimed to investigate the utility of a GLS inhibitor (GLSi). Our findings demonstrated increased glutamine abundance and a significant cytotoxic effect in AVA-resistant tumors when GLSi was administered in combination with bevacizumab.

Therapeutic implications of mitochondrial stress-induced proteasome inhibitor resistance in multiple myeloma.

The connections between metabolic state and therapy resistance in multiple myeloma (MM) are poorly understood. We previously reported that electron transport chain (ETC) suppression promotes sensitivity to the BCL-2 antagonist venetoclax. Here, we show that ETC suppression promotes resistance to proteasome inhibitors (PIs).

Driving with Both Feet: Supplementing AKG While Inhibiting BCAT1 Leads to Synthetic Lethality in GBM.

Understanding how carcinogenesis can expose cancers to synthetically lethal vulnerabilities has been an essential underpinning of development of modern anticancer therapeutics. Isocitrate dehydrogenase wild-type (IDHWT) glioblastoma multiforme (GBM), which is known to have upregulated branched-chain amino acid transaminase 1 (BCAT1) expression, has not had treatments developed to the same extent as the IDH mutant counterpart, despite making up the majority of cases. In this issue, Zhang and colleagues utilize a metabolic screen to identify α-ketoglutarate (AKG) as a synthetically lethal treatment in conjunction with BCAT1 inhibition in IDHWT GBM.

Radiotherapy-induced metabolic hallmarks in the tumor microenvironment.

Radiation is frequently administered for cancer treatment, but resistance or remission remains common. Cancer cells alter their metabolism after radiotherapy to reduce its cytotoxic effects. The influence of altered cancer metabolism extends to the tumor microenvironment (TME), where components of the TME exchange metabolites to support tumor growth.

Circulating tumor cells in precision medicine: challenges and opportunities.

The mutational and phenotypic landscape of tumors is dynamic, requiring constant monitoring of cancer patients to provide the most up-to-date and effective care. Circulating tumor cells (CTCs) obtained via liquid biopsy can provide tumor DNA, RNA, and protein information that can aid in the diagnosis, prognosis, and treatment of patients. There have been many recent studies and advances in using CTC enumeration, characterization, and expansion to provide personalized cancer treatment, validating the benefit of using CTCs as a biomarker in standard of care procedures.

Generation of systemic antitumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel.

The performance of immune-checkpoint inhibitors, which benefit only a subset of patients and can cause serious immune-related adverse events, underscores the need for strategies that induce T-cell immunity with minimal toxicity. The gut microbiota has been implicated in the outcomes of patients following cancer immunotherapy, yet manipulating the gut microbiome to achieve systemic antitumour immunity is challenging. Here we show in multiple murine tumour models that inulin-a widely consumed dietary fibre-formulated as a 'colon-retentive' orally administered gel can effectively modulate the gut microbiome in situ, induce systemic memory-T-cell responses and amplify the antitumour activity of the checkpoint inhibitor anti-programmed cell death protein-1 (α-PD-1).

The Lung Microbiome: A Central Mediator of Host Inflammation and Metabolism in Lung Cancer Patients?

Lung cancer is the leading cause of cancer-related death. Over the past 5-10 years lung cancer outcomes have significantly improved in part due to better treatment options including immunotherapy and molecularly targeted agents. Unfortunately, the majority of lung cancer patients do not enjoy durable responses to these new treatments.

Tumour-reprogrammed stromal BCAT1 fuels branched-chain ketoacid dependency in stromal-rich PDAC tumours.

Branched-chain amino acids (BCAAs) supply both carbon and nitrogen in pancreatic cancers, and increased levels of BCAAs have been associated with increased risk of pancreatic ductal adenocarcinomas (PDACs). It remains unclear, however, how stromal cells regulate BCAA metabolism in PDAC cells and how mutualistic determinants control BCAA metabolism in the tumour milieu. Here, we show distinct catabolic, oxidative and protein turnover fluxes between cancer-associated fibroblasts (CAFs) and cancer cells, and a marked reliance on branched-chain α-ketoacid (BCKA) in PDAC cells in stroma-rich tumours.

ITLN1 modulates invasive potential and metabolic reprogramming of ovarian cancer cells in omental microenvironment.

Advanced ovarian cancer usually spreads to the omentum. However, the omental cell-derived molecular determinants modulating its progression have not been thoroughly characterized. Here, we show that circulating ITLN1 has prognostic significance in patients with advanced ovarian cancer.

Cellular Location of HNF4α is Linked With Terminal Liver Failure in Humans.

Hepatocyte nuclear factor 4 alpha (HNF4α) is a transcription factor that plays a critical role in hepatocyte function, and HNF4α-based reprogramming corrects terminal liver failure in rats with chronic liver disease. In the livers of patients with advanced cirrhosis, HNF4α RNA expression levels decrease as hepatic function deteriorates, and protein expression is found in the cytoplasm. These findings could explain impaired hepatic function in patients with degenerative liver disease.

Microfluidic device for high-throughput affinity-based isolation of extracellular vesicles.

Immunoaffinity based EV isolation technologies use antibodies targeting surface markers on EVs to provide higher isolation specificity and purity compared to existing approaches. One standing challenge for researchers is how to release captured EVs from the substrate to increase downstream and biological studies. The strong binding between the antibody and antigen or the antibody and substrate is commonly unbreakable without operating at conditions outside of the critical physiological range, making the release of EVs problematic.

Electron transport chain activity is a predictor and target for venetoclax sensitivity in multiple myeloma.

The BCL-2 antagonist venetoclax is highly effective in multiple myeloma (MM) patients exhibiting the 11;14 translocation, the mechanistic basis of which is unknown. In evaluating cellular energetics and metabolism of t(11;14) and non-t(11;14) MM, we determine that venetoclax-sensitive myeloma has reduced mitochondrial respiration. Consistent with this, low electron transport chain (ETC) Complex I and Complex II activities correlate with venetoclax sensitivity.

Metabolic Reprogramming and Vulnerabilities in Cancer.

Metabolic programs are rewired in tumors to support growth, progression, and immune evasion. A wealth of work in the past decade has delineated how these metabolic rearrangements are facilitated by signaling pathways downstream of oncogene activation and tumor suppressor loss. More recently, this field has expanded to include metabolic interactions among the diverse cell types that exist within a tumor and how this impacts the immune system.