Harvard University PS-OP

Epithelial Layer Jamming in Breast Cancer Cell Migration

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. PS-OP investigators 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, it is not yet known if the transition from a jammed to an unjammed state is an essential part of organogenesis, pattern formation, and wound healing. In the pathophysiological case of malignant tissues, neither is it known if the transition from a jammed to an unjammed state is a prerequisite for invasion or metastasis. However, the discovery of cell jamming suggests a physical picture of collective cellular migration that is substantially richer than previously recognized.

This PS-OP is investigating cell jamming in the context of the 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? PS-OP researchers address this question in selected breast cancer cell lines, 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 (e.g., cellular motions, traction stresses, intercellular stresses and cellular shapes) are being critically examined through the lens of a novel quantitative theory of cell jamming.

Specific research questions being addressed 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?
Is the conventional wisdom about cell jamming 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 particular breast cancers, the hope is that the concept of cell jamming may improve the understanding of breast cancer biology and could guide novel therapeutic approaches.

Image showing a) a monolayer of human mammary epithelial cells, (b) traction stress exerted by each cell upon its substrate, and (c) intercellular stress (tension) exerted by each cell upon its neighbors.

Investigators

Jeffrey J. Fredberg, Ph.D.
Harvard University

Dr. 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.