Epithelial layer jamming in breast cancer cell migration
List of Collaborating Institutions
Boston University (Prof. Muhammad Zaman)
Dartmouth College (Prof. Zi Chen)
If cancer cells did not migrate –and instead just stayed put– then cancer in most instances would be a more manageable disease. But cancer cells do migrate, and that migration accounts for much of cancer’s morbidity and mortality. Unfortunately, we understand little about how, why, and when this aberrant cellular migration plays out. Cancer cells tend to migrate not as individual units but rather as a cellular collective –in multicellular strings, ducts, strands and clusters. We propose that a controlling factor in that collective cellular migration is a newly discovered phenomenon called “cell jamming”. From cars streaming in highway traffic to coffee beans flowing in a chute at the supermarket to cells migrating within a living tissue, a wide variety of collective systems –both inert and living– are now known to have the capacity to jam. Within a living cell cluster, in particular, cells can jam to become quiescent, solid-like, and virtually frozen in place, or instead can unjam to become mobilized, fluid-like, and migratory. In the physiological case of healthy tissues, we do not yet know if the transition from a jammed to an unjammed state is an essential part of organogenesis, pattern formation, and wound healing. And in the pathophysiological case of malignant tissues, neither do we know if the transition from a jammed to an unjammed state is a prerequisite for invasion or metastasis. We do know, however, that the discovery of cell jamming suggests a physical picture of collective cellular migration that is substantially richer than previously recognized, and we propose here to investigate cell jamming in the context of early stages of breast tumor progression. Breast cancer is representative of the wider class of cancers of epithelial origin –carcinomas– that account for the vast majority of cancers and cancer deaths.
Do epithelial cells in some circumstances behave in one way –jammed, solid-like and aggregated with little possibility of mutual cell rearrangement, escape or invasion– while in other circumstances they behave in another –unjammed, fluid-like, disaggregated and invasive? We address this question in selected breast cancer cell lines, in a variety of extracellular environments that mimic native environments, and across graded stages of the epithelial-to-mesenchymal transition. Data derived from a comprehensive suite of novel experimental probes –cellular motions, traction stresses, intercellular stresses and cellular shapes (Figure)– will be critically examined through the lens of a novel quantitative theory of cell jamming. Specific questions include:
- Do cell populations that are jammed correspond to quiescent, lower risk states whereas populations that are unjammed correspond to states that are more motile, more invasive, or more likely to metastasize?
- Conventional wisdom holds that adhesion molecules tether a cell to its immediate neighbors and thus tend to impede cellular migration. The theory of cell jamming and supporting preliminary data suggest the opposite interpretation –increased cell-cell adhesion facilitates cell unjamming and thereby promotes cellular migration. Is the conventional wisdom overly simplistic and perhaps even misleading? Does the jamming hypothesis force a fundamental rethinking of the mechano-biology of cancer cell migration and metastasis?
- How does the presence of stem-like features within cancer cell sub-populations alter the propensity for cell unjamming?
Importantly, the cell jamming hypothesis makes predictions that are mechanistic, non-trivial, and counterintuitive. If supported by the data in the instances of the particular breast cancers to be addressed here, the hope is that the concept of cell jamming may improve understanding and guide novel therapeutic approaches –not only in those particular instances, but also more generally in other cancers of epithelial origin.
- Monolayer of human mammary epithelial cells
- Traction stress exerted by each cell upon its substrate
- Intercellular stress (tension) exerted by each cell upon its neighbors
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Jeffrey J. Fredberg earned his Ph.D. in Mechanical Engineering at M.I.T. (1973) and now serves as professor of bioengineering at Harvard University in the Department of Environmental Health. His laboratory addresses basic mechanisms of cellular deformability, contractility, malleability and motility. This research focuses on airway narrowing in asthma but has spilled over to impact fields as diverse as wound healing, development, and cancer on the one hand to basic materials science and the physics of soft condensed matter on the other. Under the sponsorship of the National Heart Lung and Blood Institute, he is principal investigator of two RO1 grants and a program project (PO1).
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