Subpopulation commensalism promotes Rac1-dependent invasion of single cells via laminin-332 Public
Yoon, Sung Bo (Spring 2024)
Abstract
Phenotypic heterogeneity poses a significant hurdle for cancer treatment but is under-characterized in the context of tumor invasion. Amidst the range of phenotypic heterogeneity across solid tumor types, collectively-invading cells and single cells have been extensively characterized as independent modes of invasion, but their intercellular interactions have rarely been explored. Here, we isolate collectively-invading cells and single cells from the heterogeneous 4T1 cell line using Spatiotemporal Genomic and Cellular Analysis (SaGA) and observe distinct morphological differences between these subpopulations. Notably, collectively-invading cells exhibit prominent intercellular attachment mediated by E-cadherin, while single cells exclusively invade as detached individual cells. Furthermore, we observe extensive transcriptional and epigenetic diversity across these subpopulations. By integrating these datasets, we identify laminin-332 as a protein complex exclusively secreted by collectively-invading cells. Live cell imaging revealed that laminin-332 derived from collectively-invading cells increased the velocity and directionality of single cells. Despite collectively-invading and single cells having similar expression of the integrin α6β4 dimer, single cells demonstrated higher Rac1 activation upon laminin-332 binding to integrin α6β4. This mechanism suggests a novel commensal relationship between collectively-invading and single cells wherein collectively-invading cells promote the invasive potential of single cells through a laminin-332/Rac1 axis. To our knowledge, this finding represents the first characterization of a commensal interaction between cancer subpopulations wherein one subpopulation unilaterally provides a benefit to another subpopulation. The multi-omic workflow used to delineate this novel interaction can also be applied to other cancer subtypes to contribute towards a more comprehensive understanding of heterogeneous tumor dynamics.
Table of Contents
Table of Contents
Chapter 1: Introduction
1.1 Cancer invasion and metastasis
1.1.1. Progress and outlook on breast cancer
1.1.2. The metastatic cascade
1.1.3. Collective cell invasion
1.1.4. Single cell invasion
1.1.5. Plasticity between invasion modalities
1.2 Subpopulation interactions and dynamics
1.2.1. The genomic and epigenomic basis for phenotypic heterogeneity
1.2.2. Phenotypically-distinct subpopulations
1.2.3. Cooperation between cancer subpopulations
1.2.4. Selfish behavior in cancer
1.2.5. Parasitism and commensalism
1.3 Dissertation goals
Chapter 2: Subpopulation commensalism promotes Rac1-dependent invasion of single cells via laminin-332
2.1 Author’s Contribution and Acknowledgment of Reproduction
2.2 Abstract
2.3 Introduction
2.4 Methods
2.5 Results
2.6 Discussion
Chapter 3: Discussion and Future Directions
3.1. Collectively-invading cells and single cells are phenotypically-distinct subpopulations
3.2. Collectively-invading cells over-express laminin-332
3.3. Laminin-332 activates Rac1 single cells
3.4. Conclusions and future directions
Chapter 4: References
About this Dissertation
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