Daily Respiratory Research Analysis
Three impactful studies advanced respiratory science and care: a multi-omics analysis identified mechanistic drivers and stratification frameworks for recurrence in stage I NSCLC; a mechanistic study uncovered a RAS–POU3F3–ATP5PF axis that boosts OXPHOS and tumor aggressiveness in NSCLC; and a large prospective cohort showed that early (≤48 h) prone positioning in ventilated COVID-19 ARDS is associated with lower mortality whereas later proning is not.
Summary
Three impactful studies advanced respiratory science and care: a multi-omics analysis identified mechanistic drivers and stratification frameworks for recurrence in stage I NSCLC; a mechanistic study uncovered a RAS–POU3F3–ATP5PF axis that boosts OXPHOS and tumor aggressiveness in NSCLC; and a large prospective cohort showed that early (≤48 h) prone positioning in ventilated COVID-19 ARDS is associated with lower mortality whereas later proning is not.
Research Themes
- Translational lung cancer genomics and epigenetics
- Cancer metabolism and OXPHOS as therapeutic vulnerability
- Critical care strategies: timing of prone positioning in ARDS
Selected Articles
1. Multi-omics analyses reveal biological and clinical insights in recurrent stage I non-small cell lung cancer.
In 122 stage I NSCLC patients (57 recurrent), integrated genomics/epigenomics/transcriptomics linked solid/micropapillary histology, genomic instability, and APOBEC signatures to recurrence. PRAME was hypomethylated and overexpressed; hypomethylation at a TEAD1 site enabled PRAME transcription, and PRAME inhibition reduced metastasis via EMT gene downregulation. Multi-omics clustering stratified patients into four subgroups with distinct recurrence risks and therapeutic vulnerabilities.
Impact: This study reveals actionable mechanisms of early-stage NSCLC recurrence and proposes a robust multi-omics stratification that can guide surveillance and targeted therapy development.
Clinical Implications: PRAME hypomethylation and expression could serve as biomarkers for recurrence risk and as therapeutic targets; multi-omics stratification may inform adjuvant strategies and surveillance intensity in stage I NSCLC.
Key Findings
- Solid/micropapillary histology, genomic instability, and APOBEC-related signatures were associated with recurrence.
- PRAME was significantly hypomethylated and overexpressed in recurrent LUAD; TEAD1-site hypomethylation enabled PRAME transcription.
- PRAME inhibition reduced metastasis by downregulating EMT-related genes.
- Single-cell ecosystem changes (AT2 cells with high CNV, exhausted CD8+ T cells, Macro_SPP1) characterized recurrent tumors.
- Multi-omics clustering stratified patients into four subgroups with distinct recurrence risk and therapeutic vulnerabilities.
Methodological Strengths
- Integrated genomic, epigenomic, transcriptomic profiling of paired tumor–adjacent tissues
- Functional validation linking TEAD1-site hypomethylation to PRAME transcription and EMT/metastasis phenotypes
- Single-cell RNA-seq to define cell-type specific ecosystem changes
Limitations
- Single-cohort design with moderate sample size (n=122) may limit generalizability
- Observational nature precludes causal inference for some associations
- External validation and prospective clinical utility studies are needed
Future Directions: Prospective validation of PRAME-based biomarkers and methylation assays; testing PRAME/TEAD1-axis targeting; integrating multi-omics stratification into adjuvant trial designs for stage I NSCLC.
2. Phosphorylation of POU3F3 Mediated Nuclear Translocation Promotes Proliferation in Non-Small Cell Lung Cancer through Accelerating ATP5PF Transcription and ATP Production.
In RAS-mutant NSCLC cells, ERK1 phosphorylates POU3F3 at S393, enabling importin-β1–mediated nuclear translocation. Nuclear POU3F3 binds the ATP5PF promoter, upregulates ATP5PF and ATP production, and enhances proliferation and migration, defining a RAS–POU3F3–ATP5PF axis that drives tumor progression.
Impact: It mechanistically links oncogenic RAS signaling to OXPHOS upregulation via a druggable transcriptional axis, opening avenues to target mitochondrial bioenergetics in RAS-driven NSCLC.
Clinical Implications: Therapeutic strategies could target ERK1–POU3F3 signaling, nuclear import, or ATP5PF to disrupt OXPHOS reliance in RAS-mutant NSCLC; it also supports combining OXPHOS inhibitors with RAS/ERK pathway blockade.
Key Findings
- POU3F3 undergoes ERK1-dependent S393 phosphorylation and importin-β1–mediated nuclear translocation in RAS-mutant NSCLC cells.
- Nuclear POU3F3 binds the ATP5PF promoter, increasing ATP5PF transcription and cellular ATP production.
- Enhanced ATP5PF/ATP augments NSCLC proliferation and migration; defining a RAS–POU3F3–ATP5PF axis.
- RNA-seq and ChIP assays mechanistically supported transcriptional regulation by POU3F3.
Methodological Strengths
- Multi-pronged mechanistic approach: phosphorylation mapping, nuclear translocation assays, RNA-seq and ChIP
- Clear causal chain from RAS–ERK signaling to transcriptional activation of ATP5PF and functional phenotypes
Limitations
- Preclinical cell-line based evidence without in vivo efficacy data in the abstract
- Generalizability to non–RAS-mutant contexts and interpatient heterogeneity remains to be tested
Future Directions: Validate the axis in vivo, assess druggability (e.g., ERK1–POU3F3 interaction, import pathways, ATP5PF), and test combinations of OXPHOS and RAS/ERK inhibitors in RAS-mutant NSCLC models.
3. Effect of early and later prone positioning on outcomes in invasively ventilated COVID-19 patients with acute respiratory distress syndrome: analysis of the prospective COVID-19 critical care consortium cohort study.
Among 3131 ventilated COVID-19 patients, proning within 48 hours of IMV initiation was associated with lower 28-day (HR 0.82) and 90-day (HR 0.81) mortality versus never proned, while proning after 48 hours showed no significant mortality benefit. These findings underscore the importance of early timing for proning in ARDS management.
Impact: Defines a time-sensitive window where prone positioning confers survival benefit in ARDS due to COVID-19, informing protocols and quality metrics globally.
Clinical Implications: Implement prone positioning within 48 hours of IMV initiation when feasible; reassess late proning practices; incorporate timing into ARDS care bundles, staffing, and monitoring.
Key Findings
- Of 3131 patients, 47% were never proned, 33% within 48 h, and 20% after 48 h of IMV initiation.
- Early proning (≤48 h) was associated with reduced 28-day (HR 0.82) and 90-day mortality (HR 0.81) versus never proned.
- Proning after 48 h showed no significant association with reduced mortality.
- Analyses adjusted for confounders in a large, prospective, multinational cohort.
Methodological Strengths
- Large prospective, multinational cohort with time-window specific analyses
- Adjusted hazard models evaluating 28- and 90-day mortality
Limitations
- Observational design with potential residual confounding and practice variability
- Indication bias cannot be fully excluded (e.g., sicker patients proned later)
Future Directions: Protocolized, timing-focused trials or quasi-experiments; investigate physiologic responders to early proning; evaluate integration with neuromuscular blockade and lung-protective ventilation.