Toward understanding cancer stem cell heterogeneity in the tumor microenvironment
Abstract
The presence of heterogeneous subsets of cancer stem cells (CSCs) remains a clinical challenge. These subsets often occupy different regions in the primary tumor and have varied epithelial–mesenchymal phenotypes. Here, we devise a theoretical framework to investigate how the tumor microenvironment (TME) modulates this spatial patterning. We find that a spatial gradient of EMT-inducing signal, coupled with juxtacrine Notch-JAG1 signaling triggered by inflammatory cytokines in TME, explains this spatial heterogeneity. Finally, in vitro JAG1 knockdown in triple-negative breast cancer SUM149 cells severely restricts the growth of tumor organoid, hence validating the association between JAG1 and CSC fraction. Our results offer insights into principles of spatiotemporal patterning in TME and identify a relevant target to alleviate multiple CSC subsets: JAG1.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 26, 2018
- Source ID
- 10.1073/pnas.1815345116
Entities
People
- Eshel Ben-jacob
- Federico Bocci
- Gayathri R Devi
- Herbert Levine
- José Onuchic
- Larisa Gearhart-serna
- Marcelo Boareto
- Mariana Ribeiro
- Mohit Kumar Jolly
Organizations
- Duke University
- ETH Zurich
- Foundation for Research Support of the State of Pará
- National Institute of Environmental Health Sciences
- National Science Foundation
- Rice University
- SIB Swiss Institute of Bioinformatics
- United States Department of Defense