Cancer cell invasion is crucial for the progression to metastatic disease, particularly, of cancers from epithelial origin, carcinomas, such as breast cancer. During the transition from a non-invasive to an invasive state, cancer cells exhibit many changes in cell shape and behavior. Characterizing these changes is essential for understanding the cellular properties of invasive cancer cells, and could provide novel therapeutic strategies targeting metastasis and/or novel biomarkers that predict the potential progression to metastasis, which remains to date the cause for the high mortality rate in cancer patients. In a paper recently published in the November issue of Cancer Cell, Gus Mouneimne from the Brugge lab and collaborators characterized a cellular process that controls invasive behavior. They established that the central player in this process, which regulates the cancer cells’ cytoskeleton is a biomarker for good prognosis in breast cancer patients, and that low expression of this actin regulator correlates with high risk of metastasis. This study could have clinical implications for the management of cancer progression, especially of high-grade tumors, which are often metastatic.
This cellular process that regulates invasion involves remodeling of the actin cytoskeletal architecture. In eukaryotic cells, the organization of the actin cytoskeleton influences cell shape and behavior. In this study, the Brugge lab describes a novel mechanism of actin cytoskeletal remodeling and propose a model explaining how altering the organization of the actin cytoskeleton affects cellular shape and behavior and promotes invasion. This actin remodeling process involves three main regulators: profilin-2, an actin binding protein that brings actin monomers to polymerization sites; EVL, an actin polymerization regulator of the Ena/VASP family of proteins; and myosin, a motor protein that promotes bundling and contractility of actin filaments. This work contributes to the advancement of understanding one of the initial steps of cancer metastasis, invasion into the tumor microenvironment.
Rodents use olfactory cues for species-specific behaviors. For example, mice emit odors to attract mates of the same species but not competitors of closely related species. This implies rapid evolution of olfactory signaling, although odors and chemosensory receptors involved are unknown. In recently published paper, the Liberles Lab identified a mouse chemosignal, trimethylamine, and its olfactory receptor, trace amine-associated receptor 5 (TAAR5), to be involved in species-specific social communication (Li et al, Current Biology, 2013). Abundant (>1,000-fold increased) and sex-dependent trimethylamine production arose de novo along the Mus lineage after divergence from Mus caroli. The two-step trimethylamine biosynthesis pathway involves synergy between commensal microflora and a sex-dependent liver enzyme, flavin-containing monooxygenase 3 (FMO3), which oxidizes trimethylamine. One key evolutionary alteration in this pathway is the recent acquisition in Mus of male-specific Fmo3 gene repression. Coincident with its evolving biosynthesis, trimethylamine evokes species-specific behaviors, attracting mice but repelling rats. Attraction to trimethylamine is abolished in TAAR5 knockout mice, and furthermore, attraction to mouse scent is impaired by enzymatic depletion of trimethylamine or TAAR5 knockout. TAAR5 is an evolutionarily conserved olfactory receptor required for a species-specific behavior. Synchronized changes in odor biosynthesis pathways and odor-evoked behaviors could ensure species-appropriate social interactions.
The cellular microenvironment can affect cell behavior not only through paracrine and autocrine factors that bind to cellular receptors, but also through the mechanical properties of the tissue. For example, it is known that the mechanical properties of the cell matrix, such as stiffness, can regulate the motility of single cells. However, it is not well understood how matrix stiffness affects collective migration, or the movement of groups of cells maintained by cell-cell adhesions. Collective migration plays critical roles in development, wound healing and cancer metastasis. To elucidate whether and how microenvironmental stiffness regulates collective migration, graduate student Rosa Ng (Brugge Lab) and postdoc Achim Besser (Danuser Lab) joined forces and conducted a systematic and quantitative study of epithelial sheet migration (Ng et al, Journal of Cell Biology, 2012).
Using a modified wound-healing assay, time-lapse microscopy and a custom cell migration tracking program, the migratory behaviors of >0.5 million MCF10A epithelial cells were monitored on substrates of various compliances. Individual cells comprising the epithelial sheets migrated faster, more persistently and more directionally on stiffer substrates. Most strikingly, increasing substrate stiffness promoted the coordination in cell movements during collective migration. On stiffer substrates, cell-cell coordination extended deeper from the wound edge into the cell sheet. Such propagation of cell-cell coordination was further correlated with myosin-II activity, in a manner dependent on cadherin-mediated cell-cell adhesions. Together, the results led to a physical model of collective migration, in which cell movements are regulated by microenvironmental stiffness modulation of cell contractility, and the coupling of cell contractility between cells by cadherin adhesions give rise to coordinated movements. The Brugge and Danuser laboratories are continuing to investigate the regulation of cell motility by the interplay between microenvironmental properties, cell contractility and cell-cell adhesions, which will be important for understanding developmental processes and cancer cell metastasis.