Persistent and multiclonal malaria parasite dynamics despite extended artemether-lumefantrine treatment in children.

Standard diagnostics used in longitudinal antimalarial studies are unable to characterize the complexity of submicroscopic parasite dynamics, particularly in high transmission settings. We use molecular markers and amplicon sequencing to characterize post-treatment stage-specific malaria parasite dynamics during a 42 day randomized trial of 3- versus 5 day artemether-lumefantrine in 303 children with and without HIV (ClinicalTrials.gov number NCT03453840). The prevalence of parasite-derived 18S rRNA is >70% in children throughout follow-up, and the ring-stage marker SBP1 is detectable in over 15% of children on day 14 despite effective treatment. We find that the extended regimen significantly lowers the risk of recurrent ring-stage parasitemia compared to the standard 3 day regimen, and that higher day 7 lumefantrine concentrations decrease the probability of ring-stage parasites in the early post-treatment period. Longitudinal amplicon sequencing reveals remarkably dynamic patterns of multiclonal infections that include new and persistent clones in both the early post-treatment and later time periods. Our data indicate that post-treatment parasite dynamics are highly complex despite efficacious therapy, findings that will inform strategies to optimize regimens in the face of emerging partial artemisinin resistance in Africa.

Lessons Learned from the Connecticut Response to COVID-19 in Nursing Homes during the First 2 Years of the Pandemic.

Nearly half of all SARS-CoV-2-related deaths in the United States occurred in long-term care facilities during the early pandemic. In Connecticut, statewide mitigation of this impact involved a collaboration between the Connecticut Department of Public Health and the Yale School of Public Health, alongside existing relationships with the long-term care industry and individual facilities. This close government-academic-industry collaboration facilitated the creation of a robust COVID-19 surveillance system that allowed for real-time analysis and identification of nursing homes where outbreak support was needed. The collaboration further facilitated vaccine and booster deployment to Connecticut nursing homes at a speed that outpaced much of the country. The impact of these interventions is demonstrated through COVID-19 case and death burdens among nursing home residents and the greater Connecticut population during each wave of the pandemic. We outline the evolution and impact of these alliances and how they enabled us to prioritize facilities, interventions, and the distribution of limited resources and training throughout the pandemic. We further detail lessons learned over the first 2 years of the pandemic. Such partnerships strengthen our ability to respond effectively to public health crises and should be created and/or maintained in the face of continued pandemic threats.

Tracking antimalarial drug resistance using mosquito blood meals: a cross-sectional study.

BACKGROUND: Strong surveillance systems with wide geographic coverage are needed to detect and respond to reports of antimalarial drug resistance on the African continent. We aimed to assess the utility and feasibility of using blood-fed mosquitos (xenomonitoring) to conduct rapid surveillance of molecular markers associated with resistance in human populations. METHODS: We conducted three cross-sectional surveys in two rainy seasons and the interim dry season in southwest Burkina Faso between Oct 10, 2018, and Sept 17, 2019. We collected human blood samples and blood-fed mosquitos residing in household clusters across seven village sectors. Samples were assessed for Plasmodium falciparum with ultrasensitive quantitative PCR, genotyped for two markers of reduced drug susceptibility, pfmdr1 256A>T (Asn86Tyr) and pfcrt 227A>C (Lys76Thr), and sequenced for four markers of clonality. We assessed statistical equivalence using a 10% margin of equivalence. FINDINGS: We identified 551 infections in 1483 human blood samples (mean multiplicity of infection [MOI] 1·94, SD 1·47) and 346 infections in 2151 mosquito blood meals (mean MOI 2·2, SD 1·67). The frequency of pfmdr1 Asn86Tyr was 4% in survey 1, 2% in survey 2, and 12% in survey 3 in human samples, and 3% in survey 1, 0% in survey 2, and 8% in survey 3 in mosquito blood meals, and inter-host frequencies were statistically equivalent in surveys 1 and 2 (p<0·0001) but not Survey 3 (p=0·062) within a tolerability of 0·10. The frequency of pfcrt Lys76Thr was 16% in survey 1, 55% in survey 2, and 11% in survey 3 in humans and 40% in survey 1, 72% in survey 2, and 13% in survey 3 in mosquitos, and inter-host frequencies were equivalent in survey 3 only (p=0·032) within a tolerability of 0·10. In simulations, multiple but not preferential feeding behaviour in mosquitos reduced the accuracy of frequency estimates between hosts, particularly for markers circulating at higher frequencies. INTERPRETATION: Molecular markers in mosquito blood meals and in humans exhibited similar temporal trends but frequencies were not statistically equivalent in all scenarios. More work is needed to determine empirical and pragmatic thresholds of difference. Xenomonitoring might be an efficient tool to provide rapid information on emerging antimalarial resistance in regions with insufficient surveillance. FUNDING: National Institute of Allergy and Infectious Diseases. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Impact of Drug Exposure on Resistance Selection Following Artemether-Lumefantrine Treatment for Malaria in Children With and Without HIV in Uganda.

Artemisinin-based combination therapies (ACTs) are the primary treatment for malaria. It is essential to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ACTs in vulnerable populations at risk of suboptimal dosing. We developed a population PK/PD model using data from our previous study of artemether-lumefantrine in HIV-uninfected and HIV-infected children living in a high-transmission region of Uganda. HIV-infected children were on efavirenz-, nevirapine-, or lopinavir-ritonavir-based antiretroviral regimens, with daily trimethoprim-sulfamethoxazole prophylaxis. We assessed selection for resistance in two key parasite transporters, pfcrt and pfmdr1, over 42-day follow-up and incorporated genotyping into a time-to-event model to ascertain how resistance genotype in relation to drug exposure impacts recurrence risk. Two hundred seventy-seven children contributed 364 episodes to the model (186 HIV-uninfected and 178 HIV-infected), with recurrent microscopy-detectable parasitemia detected in 176 episodes by day 42. The final model was a two-compartment model with first-order absorption and an estimated age effect on bioavailability. Systemic lumefantrine exposure was highest with lopinavir-ritonavir, lowest with efavirenz, and equivalent with nevirapine and HIV-uninfected children. HIV status and lumefantrine concentration were significant factors associated with recurrence risk. Significant selection was demonstrated for pfmdr1 N86 and pfcrt K76 in recurrent infections, with no evidence of selection for pfmdr1 Y184F. Less sensitive parasites were able to tolerate lumefantrine concentrations ~ 3.5-fold higher than more sensitive parasites. This is the first population PK model of lumefantrine in HIV-infected children and demonstrates selection for reduced lumefantrine susceptibility, a concern as we confront the threat to ACTs posed by emerging artemisinin resistance in Africa.

The Impact of Extended Treatment With Artemether-lumefantrine on Antimalarial Exposure and Reinfection Risks in Ugandan Children With Uncomplicated Malaria: A Randomized Controlled Trial.

BACKGROUND: Artemether-lumefantrine (AL) is the most widely used artemisinin-based combination therapy in Sub-Saharan Africa and is threatened by the emergence of artemisinin resistance. Dosing is suboptimal in young children. We hypothesized that extending AL duration will improve exposure and reduce reinfection risks. METHODS: We conducted a prospective, randomized, open-label pharmacokinetic/pharmacodynamic study of extended duration AL in children with malaria in high-transmission rural Uganda. Children received 3-day (standard 6-dose) or 5-day (10-dose) AL with sampling for artemether, dihydroartemisinin, and lumefantrine over 42-day clinical follow-up. Primary outcomes were (1) comparative pharmacokinetic parameters between regimens and (2) recurrent parasitemia analyzed as intention-to-treat. RESULTS: A total of 177 children aged 16 months to 16 years were randomized, contributing 227 total episodes. Terminal median lumefantrine concentrations were significantly increased in the 5-day versus 3-day regimen on days 7, 14, and 21 (P < .001). A predefined day 7 lumefantrine threshold of 280 ng/mL was strongly predictive of recurrence risk at 28 and 42 days (P < .001). Kaplan-Meier estimated 28-day (51% vs 40%) and 42-day risk (75% vs 68%) did not significantly differ between 3- and 5-day regimens. No significant toxicity was seen with the extended regimen. CONCLUSIONS: Extending the duration of AL was safe and significantly enhanced overall drug exposure in young children but did not lead to significant reductions in recurrent parasitemia risk in our high-transmission setting. However, day 7 levels were strongly predictive of recurrent parasitemia risk, and those in the lowest weight-band were at higher risk of underdosing with the standard 3-day regimen. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number NCT03453840.

Structure-guided insights into potential function of novel genetic variants in the malaria vaccine candidate PfRh5.

The recent stall in the global reduction of malaria deaths has made the development of a highly effective vaccine essential. A major challenge to developing an efficacious vaccine is the extensive diversity of Plasmodium falciparum antigens. While genetic diversity plays a major role in immune evasion and is a barrier to the development of both natural and vaccine-induced protective immunity, it has been under-prioritized in the evaluation of malaria vaccine candidates. This study uses genomic approaches to evaluate genetic diversity in next generation malaria vaccine candidate PfRh5. We used targeted deep amplicon sequencing to identify non-synonymous Single Nucleotide Polymorphisms (SNPs) in PfRh5 (Reticulocyte-Binding Protein Homologue 5) in 189 P. falciparum positive samples from Southern Senegal and identified 74 novel SNPs. We evaluated the population prevalence of these SNPs as well as the frequency in individual samples and found that only a single SNP, C203Y, was present at every site. Many SNPs were unique to the individual sampled, with over 90% of SNPs being found in just one infected individual. In addition to population prevalence, we assessed individual level SNP frequencies which revealed that some SNPs were dominant (frequency of greater than 25% in a polygenomic sample) whereas most were rare, present at 2% or less of total reads mapped to the reference at the given position. Structural modeling uncovered 3 novel SNPs occurring under epitopes bound by inhibitory monoclonal antibodies, potentially impacting immune evasion, while other SNPs were predicted to impact PfRh5 structure or interactions with the receptor or binding partners. Our data demonstrate that PfRh5 exhibits greater genetic diversity than previously described, with the caveat that most of the uncovered SNPs are at a low overall frequency in the individual and prevalence in the population. The structural studies reveal that novel SNPs could have functional implications on PfRh5 receptor binding, complex formation, or immune evasion, supporting continued efforts to validate PfRh5 as an effective malaria vaccine target and development of a PfRh5 vaccine.

Clinical characteristics of Plasmodium falciparum infection among symptomatic patients presenting to a major urban military hospital in Cameroon.

BACKGROUND: Urban malaria has received insufficient attention in the literature. The prevalence and clinical characteristics of Plasmodium falciparum infection amongst patients presenting with suspected malaria were investigated at a major urban hospital in Douala, Cameroon with a particular focus on anaemia. METHODS: A cross-sectional, 18-week demographic and clinical survey was conducted of patients presenting to the Emergency Department of Douala Military Hospital with suspected malaria, largely defined by the presence or recent history of fever. Venous samples were tested for P. falciparum using rapid diagnostic tests and PCR, and anaemia was defined by haemoglobin level according to WHO definitions. Likelihood ratios (LR), odds ratios (OR), and population attributable risk percent (PARP) were calculated. RESULTS: Participants were ages 8 months to 86 years, 51% were women (257/503), and all districts of Douala were represented. Overall, 38.0% (n = 189/497) were anaemic, including 5.2% (n = 26/497) with severe anaemia. Anaemia prevalence was significantly higher (OR: 2.20, 95% CI 1.41-3.45) among children < 15 years (53.1%, n = 52/98) compared to adults (34%, n = 133/392). Plasmodium falciparum was detected in 37.2% by nested PCR. Among all participants, several factors were associated with clinically significant LR for P. falciparum infection, including age 10-14 years (positive LR: 3.73), living in the island district of Douala VI (positive LR: 3.41), travel to any of three northern regions (positive LR: 5.11), and high fever > 40 °C at presentation (positive LR: 4.83). Among all participants, 8.7% of anaemia was associated with P. falciparum infection, while the PARP was 33.2% among those < 15 years of age and 81.0% among 10-14-year-olds. CONCLUSIONS: The prevalence of P. falciparum infection in the urban hospital was high. Mirroring trends in many rural African settings, older children had the highest positivity rate for P. falciparum infection. Anaemia was also common in all age groups, and for those 10-14 years of age, 80% of the risk for anaemia was associated with P. falciparum infection. Malaria rates in major urban population centres can be high, and more research into the multifactorial causes of anaemia across the age spectrum are needed.

Lessons Learned From COVID-19 Contact Tracing During a Public Health Emergency: A Prospective Implementation Study.

Background: Contact tracing is a core element of the public health response to emerging infectious diseases including COVID-19. Better understanding the implementation context of contact tracing for pandemics, including individual- and systems-level predictors of success, is critical to preparing for future epidemics. Methods: We carried out a prospective implementation study of an emergency volunteer contact tracing program established in New Haven, Connecticut between April 4 and May 19, 2020. We assessed the yield and timeliness of case and contact outreach in reference to CDC benchmarks, and identified individual and programmatic predictors of successful implementation using multivariable regression models. We synthesized our findings using the RE-AIM implementation framework. Results: Case investigators interviewed only 826 (48%) of 1,705 cases and were unable to reach 545 (32%) because of incomplete information and 334 (20%) who missed or declined repeated outreach calls. Contact notifiers reached just 687 (28%) of 2,437 reported contacts, and were unable to reach 1,597 (66%) with incomplete information and 153 (6%) who missed or declined repeated outreach calls. The median time-to-case-interview was 5 days and time-to-contact-notification 8 days. However, among notified contacts with complete time data, 457 (71%) were reached within 6 days of exposure. The least likely groups to be interviewed were elderly (adjusted relative risk, aRR 0.74, 95% CI 0.61-0.89, p = 0.012, vs. young adult) and Black/African-American cases (aRR 0.88, 95% CI 0.80-0.97, pairwise p = 0.01, vs. Hispanic/Latinx). However, ties between cases and their contacts strongly influenced contact notification success (Intraclass Correlation Coefficient (ICC) 0.60). Surging caseloads and high volunteer turnover (case investigator n = 144, median time from sign-up to retirement from program was 4 weeks) required the program to supplement the volunteer workforce with paid public health nurses. Conclusions: An emergency volunteer-run contact tracing program fell short of CDC benchmarks for time and yield, largely due to difficulty collecting the information required for outreach to cases and contacts. To improve uptake, contact tracing programs must professionalize the workforce; better integrate testing and tracing services; capitalize on positive social influences between cases and contacts; and address racial and age-related disparities through enhanced community engagement.

Implementation of a volunteer contact tracing program for COVID-19 in the United States: A qualitative focus group study.

BACKGROUND: Contact tracing is an important tool for suppressing COVID-19 but has been difficult to adapt to the conditions of a public health emergency. This study explored the experiences and perspectives of volunteer contact tracers in order to identify facilitators, challenges, and novel solutions for implementing COVID-19 contact tracing. METHODS: As part of a study to evaluate an emergently established volunteer contact tracing program for COVID-19 in New Haven, Connecticut, April-June 2020, we conducted focus groups with 36 volunteer contact tracers, thematically analyzed the data, and synthesized the findings using the RE-AIM implementation framework. RESULTS: To successfully reach cases and contacts, participants recommended identifying clients' outreach preferences, engaging clients authentically, and addressing sources of mistrust. Participants felt that the effectiveness of successful isolation and quarantine was contingent on minimizing delays in reaching clients and on systematically assessing and addressing their nutritional, financial, and housing needs. They felt that successful adoption of a volunteer-driven contact tracing model depended on the ability to recruit self-motivated contact tracers and provide rapid training and consistent, supportive supervision. Participants noted that implementation could be enhanced with better management tools, such as more engaging interview scripts, user-friendly data management software, and protocols for special situations and populations. They also emphasized the value of coordinating outreach efforts with other involved providers and agencies. Finally, they believed that long-term maintenance of a volunteer-driven program requires monetary or educational incentives to sustain participation. CONCLUSIONS: This is one of the first studies to qualitatively examine implementation of a volunteer-run COVID-19 contact tracing program. Participants identified facilitators, barriers, and potential solutions for improving implementation of COVID-19 contact tracing in this context. These included standardized communication skills training, supportive supervision, and peer networking to improve implementation, as well as greater cooperation with outside agencies, flexible scheduling, and volunteer incentives to promote sustainability.

Community Trace: Rapid Establishment of a Volunteer Contact Tracing Program for COVID-19.

Contact tracing was one of the core public health strategies implemented during the first months of the COVID-19 pandemic. In this essay, we describe the rapid establishment of a volunteer contact tracing program in New Haven, Connecticut. We describe successes of the program and challenges that were faced. Going forward, contact tracing efforts can best be supported by increased funding to state and local health departments for a stable workforce and use of evidence-based technological innovations.

Investigating selected host and parasite factors potentially impacting upon seasonal malaria chemoprevention in Bama, Burkina Faso.

BACKGROUND: Since 2014, seasonal malaria chemoprevention (SMC) with amodiaquine-sulfadoxine-pyrimethamine (AQ-SP) has been implemented on a large scale during the high malaria transmission season in Burkina Faso. This paper reports the prevalence of microscopic and submicroscopic malaria infection at the outset and after the first round of SMC in children under 5 years old in Bama, Burkina Faso, as well as host and parasite factors involved in mediating the efficacy and tolerability of SMC. METHODS: Two sequential cross-sectional surveys were conducted in late July and August 2017 during the first month of SMC in a rural area in southwest Burkina Faso. Blood smears and dried blood spots were collected from 106 to 93 children under five, respectively, at the start of SMC and again 3 weeks later. Malaria infection was detected by microscopy and by PCR from dried blood spots. For all children, day 7 plasma concentrations of desethylamodiaquine (DEAQ) were measured and CYP2C8 genetic variants influencing AQ metabolism were genotyped. Samples were additionally genotyped for pfcrt K76T and pfmdr1 N86Y, molecular markers associated with reduced amodiaquine susceptibility. RESULTS: 2.8% (3/106) of children were positive for Plasmodium falciparum infection by microscopy and 13.2% (14/106) by nested PCR within 2 days of SMC administration. Three weeks after SMC administration, in the same households, 4.3% (4/93) of samples were positive by microscopy and 14.0% (13/93) by PCR (p = 0.0007). CYP2C8*2, associated with impaired amodiaquine metabolism, was common with an allelic frequency of 17.1% (95% CI 10.0-24.2). Day 7 concentration of DEAQ ranged from 0.48 to 362.80 ng/mL with a median concentration of 56.34 ng/mL. Pfmdr1 N86 predominated at both time points, whilst a non-significant trend towards a higher prevalence of pfcrt 76T was seen at week 3. CONCLUSION: This study showed a moderate prevalence of low-level malaria parasitaemia in children 3 weeks following SMC during the first month of administration. Day 7 concentrations of the active DEAQ metabolite varied widely, likely reflecting variability in adherence and possibly metabolism. These findings highlight factors that may contribute to the effectiveness of SMC in children in a high transmission setting.

p63 and SOX2 Dictate Glucose Reliance and Metabolic Vulnerabilities in Squamous Cell Carcinomas.

Squamous cell carcinoma (SCC), a malignancy arising across multiple anatomical sites, is responsible for significant cancer mortality due to insufficient therapeutic options. Here, we identify exceptional glucose reliance among SCCs dictated by hyperactive GLUT1-mediated glucose influx. Mechanistically, squamous lineage transcription factors p63 and SOX2 transactivate the intronic enhancer cluster of SLC2A1. Elevated glucose influx fuels generation of NADPH and GSH, thereby heightening the anti-oxidative capacity in SCC tumors. Systemic glucose restriction by ketogenic diet and inhibiting renal glucose reabsorption with SGLT2 inhibitor precipitate intratumoral oxidative stress and tumor growth inhibition. Furthermore, reduction of blood glucose lowers blood insulin levels, which suppresses PI3K/AKT signaling in SCC cells. Clinically, we demonstrate a robust correlation between blood glucose concentration and worse survival among SCC patients. Collectively, this study identifies the exceptional glucose reliance of SCC and suggests its candidacy as a highly vulnerable cancer type to be targeted by systemic glucose restriction.

Glucose Transporter 1 Gene Variants Predict the Prognosis of Patients with Early-Stage Non-small Cell Lung Cancer.

BACKGROUND: This study was conducted to investigate whether polymorphisms of glucose transporter 1 (GLUT1) gene are associated with the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. METHODS: Five single nucleotide polymorphisms (SNPs) in GLUT1 were investigated in a total of 354 patients with NSCLC who underwent curative surgery. The association of the SNPs with patients' survival was analyzed. RESULTS: Among the five SNPs investigated, two SNPs (GLUT1 rs3820589T > A and rs4658G > C) were significantly associated with OS in multivariate analyses. GLUT1 rs3820589T > A was associated with significantly better OS (adjusted hazard ratio [aHR] = 0.57, 95% confidence interval [CI] = 0.34-0.94, P = 0.03, under dominant model), and rs4658G > C was associated with significantly worse OS (aHR = 1.91, 95% CI = 1.09-3.33, P = 0.02, under recessive model). In the stratified analysis by tumor histology, the effect of these SNPs on OS was only significant in squamous cell carcinoma but not in adenocarcinoma. When the two SNPs were combined, OS decreased as the number of bad genotypes increased (Ptrend = 4 × 10-3). CONCLUSIONS: This study suggests that genetic variation in GLUT1 may be useful in predicting survival of patients with early stage NSCLC.

Targeting Hypoxia-Inducible Factor-1α/Pyruvate Dehydrogenase Kinase 1 Axis by Dichloroacetate Suppresses Bleomycin-induced Pulmonary Fibrosis.

Hypoxia has long been implicated in the pathogenesis of fibrotic diseases. Aberrantly activated myofibroblasts are the primary pathological driver of fibrotic progression, yet how various microenvironmental influences, such as hypoxia, contribute to their sustained activation and differentiation is poorly understood. As a defining feature of hypoxia is its impact on cellular metabolism, we sought to investigate how hypoxia-induced metabolic reprogramming affects myofibroblast differentiation and fibrotic progression, and to test the preclinical efficacy of targeting glycolytic metabolism for the treatment of pulmonary fibrosis. Bleomycin-induced pulmonary fibrotic progression was evaluated in two independent, fibroblast-specific, promoter-driven, hypoxia-inducible factor (Hif) 1A knockout mouse models and in glycolytic inhibitor, dichloroacetate-treated mice. Genetic and pharmacological approaches were used to explicate the role of metabolic reprogramming in myofibroblast differentiation. Hypoxia significantly enhanced transforming growth factor-ß-induced myofibroblast differentiation through HIF-1α, whereas overexpression of the critical HIF-1α-mediated glycolytic switch, pyruvate dehydrogenase kinase 1 (PDK1) was sufficient to activate glycolysis and potentiate myofibroblast differentiation, even in the absence of HIF-1α. Inhibition of the HIF-1α/PDK1 axis by genomic deletion of Hif1A or pharmacological inhibition of PDK1 significantly attenuated bleomycin-induced pulmonary fibrosis. Our findings suggest that HIF-1α/PDK1-mediated glycolytic reprogramming is a critical metabolic alteration that acts to promote myofibroblast differentiation and fibrotic progression, and demonstrate that targeting glycolytic metabolism may prove to be a potential therapeutic strategy for the treatment of pulmonary fibrosis.

A New Perspective on the Heterogeneity of Cancer Glycolysis.

Tumors are dynamic metabolic systems which 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 tumorigenecity. 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. In this review, we will discuss diverse oncogenic and molecular alterations that drive distinct and heterogeneous glucose metabolism in cancers. We will also discuss a new perspective on how aberrantly altered glycolysis in response to oncogenic signaling is further influenced and remodeled by dynamic metabolic interaction with surrounding tumor-associated stromal cells.

Lung squamous cell carcinoma exhibits a targetable glucose dependency unique among non-small cell lung cancers.

Cancer cells consume high amounts of glucose for their cellular bioenergetic and anabolic requirements, relying on glucose to fuel their growth. We recently reported that lung squamous cell carcinoma, a major subtype of non-small cell lung cancer (NSCLC), exhibits remarkably elevated glucose transporter GLUT1 (encoded by SLC2A1) expression and glucose dependency, while another subtype of NSCLC, lung adenocarcinoma, shows significant glucose independence. Our findings highlight the metabolic heterogeneity of glucose metabolism among lung cancer subtypes, which can be exploited for targeted lung cancer therapies.

The distinct metabolic phenotype of lung squamous cell carcinoma defines selective vulnerability to glycolytic inhibition.

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. Here, we perform an integrative analysis of human NSCLC tumour samples, patient-derived xenografts, murine model of NSCLC, NSCLC cell lines and The Cancer Genome Atlas (TCGA) and reveal a markedly elevated expression of the GLUT1 glucose transporter in lung SqCC, which augments glucose uptake and glycolytic flux. 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.