Our lab investigates how cancer cells acquire the ability to invade their surroundings, a key early step in the lethal progression to metastasis. The majority of human cancers occurs in epithelial tissue in which proliferation and migration of normal epithelial cells are ordinarily held in check. When these inhibitions are broken or disrupted, cells proliferate chaotically, forming a primary tumor mass, and gain the capacity to migrate and invade into the surrounding matrix, ultimately reaching and infiltrating nearby blood vessels through which they travel and colonize secondary sites.
We investigate how changes within cells in regulatory pathways (e.g., EGFR and TGFβ signaling, MAP kinase, E-cadherin, apical-basal regulator PARD3, Notch) and in the surrounding microenvironment conspire to transform normal cells into invasive cancer cells. We seek to identify robust therapeutic strategies to target cancer cells whose heterogeneity and plasticity make them a "moving target". Because the properties of cancer cells are non-uniform and closely coupled to their microenvironmental context, we image and analyze single-cell behaviors in microscale environments that are engineered to mimic, isolate and tune critical features of their complex in vivo tumor microenvironment.
Sliding behavior - getting around obstacles to migrate in a spatially-constrained, crowded environment
Breast cancer cells migrate and invade along collagen fibers in vivo. While fiber tracks provide pathways for migration, they also present a challenge in a crowded microenvironment with numerous cells and cell types. When a migrating cancer cell encounters others cells along a spatially-restrictive track, the "choices" it makes will determine the efficiency of invasion. If the cancer cell halts or reverses direction upon contact with other cells, invasion will be inefficient. Conversely, if cells maintain direction and are able to circumnavigate to “slide” past other cells in their path, they are likely to increase their dispersion efficiency.
We have found that disruptions in pathways that promote cancer in vivo --- cell polarity machinery (PARD3) and ErbB2 signaling -- enables sliding behavior along micropatterned fiber-like tracks [Milano 2016a; Milano 2016b]. In contrast, non-transformed cells with functional polarity machinery reverse direction when they encounter each other. Moreover, successive perturbations enable cells to slide more efficiently on progressively narrower fiber-like tracks. Thus, accumulating cell-intrinsic genetic perturbations enables cells to overcome extrinsic spatial constraints to slide. Ongoing work focuses on understanding the mechanisms involved in sliding behavior and elucidating the role of sliding during invasion in vivo.
Please refer to recent publications for details.
Integrative morphodynamics: design principles for engineering living tissues, November 2009.
Design principles for engineering living tissues have the potential to revolutionize medicine. A principal challenge, however, is our nascent understanding of how to program the behavior of individual human cells and how to coordinate their interactions within a complex microenvironment. Download complete PDF.