Metabolic programming defines oxygen sensitive subpopulation hierarchies and patterning in collective invasion. Restricted; Files & ToC
Matsuk, Veronika (Fall 2025)
Abstract
Cancer metastasis remains the leading cause of cancer-related mortality, yet our understanding of the cellular and molecular mechanisms that enable tumor dissemination remain incomplete. Collective invasion, a collaborative process where heterogeneous subpopulations move together while maintaining cell-cell junctions, represents a major mode of metastatic dissemination in carcinomas. These invasive projections are composed of heterogeneous subpopulations that cooperate to sustain invasion and survival. Previous studies in non-small cell lung cancer (NSCLC) have characterized these cells as “leaders” and “followers”; however, this binary framework fails to capture the full spectrum of intratumoral heterogeneity that underpins collective invasion and metastatic progression. This dissertation moves beyond the traditional leader-follower paradigm to define the molecular and metabolic phenotypes of NSCLC subpopulations and elucidates how distinct cellular subpopulations interact to drive collective invasion and metastasis. By integrating molecular analyses with mitochondria-focused metabolic profiling, we identified three NSCLC subpopulations where each is distinguished by unique IL13RA2 cell surface expression and mitochondrial polarization states: IL13RA2-positive with low mitochondrial polarization (+/Low), IL13RA2-negative with low mitochondrial polarization (-/Low), and IL13RA2-negative with high mitochondrial polarization (-/High). These subpopulations exhibit distinct invasive behaviors that are influenced by microenvironmental cues, including oxygen availability. While -/Low cells are the most invasive in 21% oxygen, -/High cells, characterized by elevated mitochondrial load and oxidative metabolism, assume a dominant invasive phenotype under 1% oxygen. This shift suggests that metabolic adaptability, rather than a fixed invasive phenotype, can drive opportunistic invasion and spatial patterning within the tumor microenvironment. Extending these findings in vivo, we demonstrate that these molecular and metabolic heterogeneities are preserved during NSCLC progression and are functionally significant. IL13RA2- subpopulations exhibit enhanced metastatic colonization of the lung and liver compared to their IL13RA2+ counterparts, while –/High cells display advantages in secondary site colonization. Moreover, reducing subpopulation heterogeneity through lower subcutaneous implantation densities diminished metastatic progression, underscoring heterogeneity as a driver of tumor progression. Together, these findings redefine collective invasion as an integration of cooperative metabolic and phenotypic heterogeneities. Distinct subpopulations engage in complementary roles that enable tumors to balance metabolic demands with environmental constraints. This work establishes a new framework for understanding tumor heterogeneity as a fundamental and functional property of cancer progression.
Table of Contents
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File download under embargo until 12 July 2026 | 2025-11-30 12:26:06 -0500 | File download under embargo until 12 July 2026 |
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