Metabolic programming defines oxygen-sensitive subpopulation hierarchies and patterning in collective invasion

Area of Science:

• Oncology
• Cell Biology
• Cancer Research

Background:

• Phenotypic heterogeneity, characterized by molecular and behavioral variations, significantly impacts collective invasion and tumor progression.
• Understanding metabolic heterogeneity in non-small cell lung cancer (NSCLC) is crucial for deciphering invasion dynamics.

Purpose of the Study:

• To investigate how metabolic heterogeneity in NSCLC influences invasion and pack patterning.
• To identify biomarkers for invasive potential and isolate distinct subpopulations.

Main Methods:

• Utilized flow cytometry and integrated cell surface markers (IL13RA2) with mitochondrial membrane potential (TMRM) to isolate subpopulations.
• Performed 2D and 3D analyses to assess invasion patterns, mitochondrial polarity, and transcriptional programs.
• Evaluated the influence of oxygen tension and subpopulation composition on collective invasion.

Main Results:

• Identified IL13RA2 as a biomarker for invasive potential in NSCLC.
• Isolated three distinct subpopulations with varying mitochondrial polarity and oxygen sensitivity.
• Observed distinct invasion patterns (contiguous packs, chains) in 3D, influenced by oxygen availability and metabolic differences.
• Recombined subpopulations exhibited stochastic and cooperative dynamics dependent on composition and oxygen levels.

Conclusions:

• Phenotypic and metabolic heterogeneity, population composition, and oxygen availability collectively pattern invasion packs.
• The molecular approach integrating cell surface and metabolic characteristics enables isolation of unique subpopulations driving collective invasion.