Discovery and Targeting of Strict Glucose Reliance in Lung Squamous Cell Carcinoma and Taxonomic and Genomic Ecology of Recurrent Urinary Tract Infection



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Tumors are dynamic metabolic systems which require highly augmented metabolic fluxes and nutrient needs to support cellular proliferation and physiological function. For many years, a central hallmark of tumor metabolism has emphasized a uniformly elevated aerobic glycolysis as a critical feature of tumorigenicity. This led to extensive efforts of targeting glycolysis in human cancers. However, clinical attempts to target glycolysis and glucose metabolism have proven to be challenging. Recent advancements revealing a high degree of metabolic heterogeneity and plasticity embedded among various human cancers may paint a new picture of metabolic targeting for cancer therapies with a renewed interest in glucose metabolism. Adenocarcinoma (ADC) and squamous cell carcinoma (SqCC) are the two predominant subtypes of non-small cell lung cancer (NSCLC) and are distinct in their histological, molecular and clinical presentation. However, metabolic signatures specific to individual NSCLC subtypes remain unknown. We show that a critical reliance on glycolysis renders lung SqCC vulnerable to glycolytic inhibition, while lung ADC exhibits significant glucose independence. Clinically, elevated GLUT1-mediated glycolysis in lung SqCC strongly correlates with high 18F-FDG uptake and poor prognosis. This previously undescribed metabolic heterogeneity of NSCLC subtypes implicates significant potential for the development of diagnostic, prognostic and targeted therapeutic strategies for lung SqCC, a cancer for which existing therapeutic options are clinically insufficient. Recent advances in the analysis of microbial communities colonizing the human body have identified a resident microbial community in the human urinary tract (UT). Compared to many other microbial niches, the human UT harbors a relatively low biomass. Studies have identified many genera and species that may constitute a core UT microbiome. However, the contribution of the UT microbiome to urinary tract infection (UTI) and recurrent UTI (rUTI) pathobiology is not yet clearly understood. Evidence suggests that commensal species within the UT and urogenital tract (UGT) microbiomes, such as Lactobacillus crispatus, may act to protect against uropathogen colonization. However, the mechanisms and fundamental biology of the UT and UGT microbiome-host relationship are not understood. Urinary tract infections (UTIs) are the most commonly reported infections in adult women and have high rates of recurrence, especially in postmenopausal women. Recurrent UTI (rUTI) greatly reduces quality of life, places a significant burden on the healthcare system, and contributes to antimicrobial resistance. Because treatment of rUTI by long-term antibiotic therapy is often ineffective or poorly tolerated in elderly women, new therapies must be developed. The molecular basis of rUTI, especially in postmenopausal women, has remained unclear because modeling rUTI in mice is difficult, and human data are limited. Invasion of the urothelium and induction of host inflammation are hypothesized to be key mechanisms by which bacterial pathogens cause rUTI. We provide direct evidence that bacteria reside in the bladder wall of postmenopausal rUTI patients and that diverse bacterial species can be isolated from the bladder tissue. These data provide conclusive evidence that bacteria invade the human urothelium and suggest that diverse bacterial species and the adaptive immune response play important roles in rUTI in humans. The microbial ecology associated with rUTI remains uncharacterized. The ability to measure and quantify the composition of the UT microbiome has been enabled through the development of next generation sequencing and bioinformatic platforms that allow for the unbiased detection of resident microbial DNA. While numerous studies have used 16S rRNA amplicon sequencing to taxonomically profile the microbial taxonomic ecology of the human urogenital microbiome in health and disease, few whole genome metagenomic (WGM) datasets have been generated to profile the genomic ecology of this understudied niche. We set out to study the urogenital microbiome of PM women through WGM to not only determine the taxonomic ecology (microbial species present) of rUTI but also the genomic ecology (microbial genes present) that may contribute to rUTI pathobiology and susceptibility. When completed, this metagenomic dataset along with detailed clinical metadata and a curated biobank of more than 2000 patient-derived isolates will serve a larger role as a publicly available resource that will further the field’s understanding of rUTI and the PM urogenital microbiome. Translating technological advances into clinical insight will require further study of the microbial and genomic ecology of the UT and UGT microbiomes in both health and disease. Future diagnostic, prognostic, and therapeutic options for the management of UTI may soon incorporate efforts to measure, restore and/or preserve the native, healthy ecology of the UT and UGT microbiomes.



Tumors, Cancer, Glycolysis, Metagenomics, Urinary tract infections