Besaiz Jose Sánchez-Sánchez

Epithelial tissues serve as critical physical barriers that protect organs, making their efficient repair essential upon damage. To achieve this, tissues must quickly react, forcing cells to rearrange and accommodate to achieve rapid wound closure. In the Drosophila wing disc, we previously showed how tissue fluidisation accelerated wound healing in 2D. However, the 3D aspect of tissue repair remains poorly understood. Here, we uncover a new mechanism that facilitates tissue repair through changing cell height. We find actomyosin contractile cables at the wound edge connecting the apical and basal cell surfaces, which indent the apical side of the tissue and deform the basement membrane, respectively. To assess the role of the different repair mechanisms, we develop a 3D vertex model allowing independent apical, lateral and basal behaviours. The model predicts that lateral cables play a role in regulating planar cell-cell intercalations, confirmed by Drosophila mutations affecting cell deformations. Our results demonstrate that lateral cables cooperate with the apical purse string to drive 3D cell shape changes and planar cell-cell intercalations for efficient wound repair.

Cells are thought to adopt mechanistically distinct migration modes depending on cell-type and environmental factors. These modes are assumed to be driven by mutually exclusive actin cytoskeletal organizations, which are either lamellar (flat, branched network) or cortical (crosslinked to the plasma membrane). Here we exploit Drosophila macrophage (hemocyte) developmental dispersal to reveal that these cells maintain both a lamellar actin network at their cell front and a cortical actin network at the rear. Loss of classical actin cortex regulators, such as Moesin, perturb hemocyte morphology and cell migration. Furthermore, cortical and lamellipodial actin networks are interregulated. Upon phosphorylation and binding to the plasma membrane, Moesin is advected to the rear by lamellar actin flow. Simultaneously, the cortical actin network feeds back on the lamella to help regulate actin flow speed and leading-edge dynamics. These data reveal that hemocyte motility requires both lamellipodial and cortical actin architectures in homeostatic equilibrium.

In this study, we found that in the adipose tissue of wildtype animals, insulin and TGF‐β signalling converge via a BMP antagonist short gastrulation (sog) to regulate ECM remodelling. In tumour bearing animals, Sog also modulates TGF‐β signalling to regulate ECM accumulation in the fat body. TGF‐β signalling causes ECM retention in the fat body and subsequently depletes muscles of fat body‐derived ECM proteins. Activation of insulin signalling, inhibition of TGF‐β signalling, or modulation of ECM levels via SPARC, Rab10 or Collagen IV in the fat body, is able to rescue tissue wasting in the presence of tumour. Together, our study highlights the importance of adipose ECM remodelling in the context of cancer cachexia.

Cancer cachexia is a wasting disease suffered by advanced stage cancer patients and ultimately causes ∼30% of cancer mortalities. Clinical observations have shown that extracellular matrix (ECM) remodelling which leads to fibrosis in the adipose tissue is a key feature of cancer cachexia. However, the molecular regulators of adipose ECM remodelling are not known and how this leads to muscle wasting is unclear. In this study, using a Drosophila cachexia model, we found that in the adipose tissue of both wildtype and tumour bearing animals, insulin and TGF-β signalling converge via a BMP antagonist short gastrulation ( sog ) to regulate ECM remodelling. In tumour bearing animals, the aberrant ECM accumulation in the fatbody, contributes towards muscle detachment by preventing ECM secretion and subsequently depleting muscles of fatbody-secreted ECM proteins. Strikingly, activation of insulin signalling, inhibition of TGF-β signalling, or modulation of ECM secretion via SPARC or Rab10 in the fatbody, was able to rescue tissue wasting in the presence of tumour. Together, our study highlights the importance of adipose ECM remodelling in the context of cancer cachexia.

Summary: The forces controlling tissue morphogenesis are attributed to cellular-driven activities and any role for extracellular matrix (ECM) is assumed to be passive. However, all polymer networks, including ECM, can theoretically develop autonomous stresses during their assembly. Here we examine the morphogenetic function of an ECM prior to reaching homeostatic equilibrium by analyzing de novo ECM assembly during Drosophila ventral nerve cord (VNC) condensation. Asymmetric VNC shortening and a rapid decrease in surface area correlate with exponential assembly of Collagen-IV (Col4) surrounding the tissue. Concomitantly, a transient developmentally-induced Col4 gradient leads to coherent long-range flow of ECM, which equilibrates the Col4 network. Finite element analysis and perturbation of Col4 network formation through the generation of dominant Col4-truncations that affect assembly, reveals that VNC morphodynamics is driven by a sudden increase in ECM-driven surface tension. These data highlight that ECM assembly stress and associated network instabilities can actively participate in tissue morphogenesis.

In this paper, a novel method for interaction detection is presented to compare the contact dynamics of macrophages in the Drosophila embryo. The study is carried out by a framework called macrosight, which analyses the movement and interaction of migrating macrophages. The framework incorporates a segmentation and tracking algorithm into analysing the motion characteristics of cells after contact. In this particular study, the interactions between cells is characterised in the case of control embryos and Shot mutants, a candidate protein that is hypothesised to regulate contact dynamics between migrating cells. Statistical significance between control and mutant cells was found when comparing the direction of motion after contact in specific conditions. Such discoveries provide insights for future developments in combining biological experiments with computational analysis.

This paper compares the contact-repulsion movement of mutant and wild-type macrophages using a novel interaction detection mechanism. The migrating macrophages are observed in Drosophila embryos. The study is carried out by a framework called macrosight , which analyses the movement and interaction of migrating macrophages. The framework incorporates a segmentation and tracking algorithm into analysing motion characteristics of cells after contact. In this particular study, the interactions between cells is characterised in the case of control embryos and Shot3 mutants , where the cells have been altered to suppress a specific protein, looking to understand what drives the movement. Statistical significance between control and mutant cells was found when comparing the direction of motion after contact in specific conditions. Such discoveries provide insights for future developments in combining biological experiments to computational analysis. Cell Segmentation, Cell Tracking, Macrophages, Cell Shape, Contact Analysis