Search for: All records

Cell migration is critical throughout a multicellular organism’s life from embryogenesis to immune response and tissue repair and can even go aberrantly wrong in diseases like metastatic cancer. In vitro, graded concentrations of diffusible chemoattractants can guide migrating cells, but less is known about chemoattractant distribution and chemotaxis within living organisms, which have complex tissue geometries. Using the border cells, which migrate collectively in the Drosophila egg chamber during oogenesis, we studied how tissue structure affects chemotaxis in vivo. Live-imaged border cells exhibited variations in their chemotactic migration, which correlated positionally within distinct tissue architectures, specifically acellular gaps at cell-cell intersections. To determine how different regions in the egg chamber’s geometry affect chemical cues, we developed a partial differential equation (PDE) model of chemoattractant distribution within a relevant in silico domain. Using a hybrid mathematical model that couples the chemoattractant PDE and an agent-based motion of the cluster, we found that larger extracellular volumes within intersections could locally dampen chemoattractant gradient magnitudes and slow cluster speed in simulations. In vivo, in response to genetically increasing the levels of a chemoattractant, PDGF- and VEGF-related factor 1, border cells exhibited delayed migration and behaved differently within specific architectural regions, consistent with results in silico. We next altered the architectural regions in the migration domain in half pint (hfp) mutant egg chambers and observed migration behaviors that still correlated with tissue features. Importantly, the abnormal tissue geometry was sufficient to rescue defects due to high levels of chemoattractant and resulted in punctual border cell migration indicating chemoattractant distribution can depend on tissue structure. Our modeling data indicate that chemoattractants are more concentrated in certain tissue architectures and dispersed in other regions, likely informing cell migration speeds and favoring clustered cell movements in tissue that contain varied architectures in vivo. Our results shed light on the intricate interplay between tissue geometry and the local distribution of important signaling molecules in orchestrating the essential process of cell migration. 

ABSTRACT Migratory cells – either individually or in cohesive groups – are critical for spatiotemporally regulated processes such as embryonic development and wound healing. Their dysregulation is the underlying cause of formidable health problems such as congenital abnormalities and metastatic cancers. Border cell behavior during Drosophila oogenesis provides an effective model to study temporally regulated, collective cell migration in vivo. Developmental timing in flies is primarily controlled by the steroid hormone ecdysone, which acts through a well-conserved, nuclear hormone receptor complex. Ecdysone signaling determines the timing of border cell migration, but the molecular mechanisms governing this remain obscure. We found that border cell clusters expressing a dominant-negative form of ecdysone receptor extended ineffective protrusions. Additionally, these clusters had aberrant spatial distributions of E-cadherin (E-cad), apical domain markers and activated myosin that did not overlap. Remediating their expression or activity individually in clusters mutant for ecdysone signaling did not restore proper migration. We propose that ecdysone signaling synchronizes the functional distribution of E-cadherin, atypical protein kinase C (aPKC), Discs large (Dlg1) and activated myosin post-transcriptionally to coordinate adhesion, polarity and contractility and temporally control collective cell migration. 

Over the past three-decades, Janus kinase (Jak) and signal transducer and activator of transcription (STAT) signaling has emerged as a paradigm to understand the involvement of signal transduction in development and disease pathology. At the molecular level, cytokines and interleukins steer Jak/STAT signaling to transcriptional regulation of target genes, which are involved in cell differentiation, migration, and proliferation. Jak/STAT signaling is involved in various types of blood cell disorders and cancers in humans, and its activation is associated with carcinomas that are more invasive or likely to become metastatic. Despite immense information regarding Jak/STAT regulation, the signaling network has numerous missing links, which is slowing the progress towards developing drug therapies. In mammals, many components act in this cascade, with substantial cross-talk with other signaling pathways. In Drosophila, there are fewer pathway components, which has enabled significant discoveries regarding well-conserved regulatory mechanisms. Work across species illustrates the relevance of these regulators in humans. In this review, we showcase fundamental Jak/STAT regulation mechanisms in blood cells, stem cells, and cell motility. We examine the functional relevance of key conserved regulators from Drosophila to human cancer stem cells and metastasis. Finally, we spotlight less characterized regulators of Drosophila Jak/STAT signaling, which stand as promising candidates to be investigated in cancer biology. These comparisons illustrate the value of using Drosophila as a model for uncovering the roles of Jak/STAT signaling and the molecular means by which the pathway is controlled.