# Implications of metabolic heterogeneity on collective lung cancer cell invasion

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $447,483

## Abstract

Project Summary
Most studies investigate whole cancer cell populations and rarely address how single cells or sub-populations
cooperate to promote their survival and spread. This is especially true in the context of metabolism, where tumors
harbor distinct sub-populations of glycolytic and oxidative cells forged in part by microenvironmental pressures.
How this metabolic heterogeneity drives tumor invasion and metastasis is an unexplored area and requires
approaches that can isolate these specific cancer cell sub-populations. This multi-PI application in lung
adenocarcinoma attempts to address this by determining how metabolically heterogeneous cancer cell sub-
populations function and cooperate to drive invasion and metastasis. We build upon our published image-guided
genomics technology (SaGA) to extract living and phenotypically defined cell sub-populations within collectively
invading packs. We used SaGA to deconstruct the lung cancer collective invasion pack, which is comprised of
hierarchical groups of invasive leader and proliferative follower cells invading as a cohesive unit. Our published
and preliminary data show that follower cells consume twice as much glucose as leaders, and rely on glycolysis
and the oxidative pentose phosphate pathway (PPP) to maintain their proliferative state. By simply disrupting
the glucose transporter, GLUT1, followers become invasive and take on a leader-like phenotype. In contrast,
leaders rely on oxidative phosphorylation (OXPHOS) via pyruvate dehydrogenase (PDH) activity to drive
invasion, where disrupting PDH creates a more follower-like phenotype. These data lead to our overarching
hypothesis that metabolic heterogeneity sustained by differential GLUT1 and PDH-driven metabolism facilitates
lung cancer metastasis by maintaining distinct phenotypes in the collective invasion pack. We propose that this
metabolic heterogeneity warrants a co-targeting therapeutic approach that disrupts both metabolic populations
to inhibit metastasis. Thus, the objective of this proposal is to 1) elucidate the molecular basis and mechanistic
underpinnings of how metabolic heterogeneity drives collective invasion and 2) test if co-targeting different
metabolic sub-populations limits metastasis. We propose that these studies will directly impact our understanding
of how metabolic heterogeneity sustains cooperativity to promote collective invasion/metastasis.

## Key facts

- **NIH application ID:** 10143682
- **Project number:** 1R01CA247367-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Adam I. Marcus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $447,483
- **Award type:** 1
- **Project period:** 2021-04-05 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10143682

## Citation

> US National Institutes of Health, RePORTER application 10143682, Implications of metabolic heterogeneity on collective lung cancer cell invasion (1R01CA247367-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10143682. Licensed CC0.

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