Biology subjects

Bakopoulos, D.

Publications and source records attributed to Bakopoulos, D..

3 recordsLinked to original sources

bioRxiv2023

Convergent Insulin and TGF-β signalling drives cancer cachexia by promoting aberrant fatbody ECM accumulation in a Drosophila tumour model

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-{beta} 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-{beta} 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.

developmental biology↗

bioRxiv2020

Drosophila macrophage self-renewal is regulated by transient expression of PDGF- and VEGF-related factor 2

Macrophages are an ancient animal blood cell lineage critical for tissue homeostasis and defence against pathogens. Until recently, their numbers were thought to be sustained solely by specialised hematopoietic organs. It is now clear that many macrophages are instead replenished by self-renewal, yet the signals that regulate this remain poorly understood. In Drosophila melanogaster, macrophages (known as plasmatocytes) undergo a phase of rapid population expansion via self-renewal, making Drosophila an attractive model for revealing the signals and regulatory mechanisms involved. However, no central self-renewal pathway has been identified in Drosophila. Here, we investigated the PDGF-/VEGF-receptor pathway as a candidate for playing this role. Analysis of larvae deficient for each of the three PDGF-/VEGF-receptor ligands Pvf1-3 revealed Pvf2 as a major driver of macrophage self-renewal in Drosophila. We further found that only a small proportion of blood cells express Pvf2, and knockdown experiments implicate these cells as a major source of Pvf2 in self-renewal. Lineage tracing studies support the idea that Pvf2 expression in blood cells occurs transiently throughout the macrophage self-renewal period, and in response to an as yet unidentified cue. These data define the regulation of Pvf2 expression in blood cells as a central mechanism by which macrophage self-renewal is controlled. Given the strong parallels that exist between Drosophila and vertebrate macrophage systems, it is likely that similar mechanisms are at play across animal phyla.

genetics↗

bioRxiv2020

Insulin-like signalling influences the coordination of Drosophila larval hemocyte number with body size

Blood cells, known as hemocytes in invertebrates, play important and conserved roles in immunity, wound healing and tissue remodelling. The control of hemocyte number is therefore critical to ensure these functions are not compromised, and studies using Drosophila are proving useful for understanding how this occurs. Recently, the well characterised embryonic patterning gene, torso-like (tsl), was identified as being required both for normal hemocyte number and for providing immunity against certain pathogens. Here, we report that Tsl is required specifically during the larval phase of hematopoiesis, and that the reduced hemocyte number found in tsl mutant larvae is likely the result of a reduced larval growth rate and compromised insulin signalling. Consistent with this, we find that impairing insulin-mediated growth, either by nutrient deprivation or genetically, results in fewer hemocytes. This is likely the result of impaired insulin-like signalling in the hemocytes themselves since modulation of Insulin-like Receptor (InR) activity specifically in hemocytes causes concomitant changes to their population size in developing larvae. Taken together, our work reveals the strong relationship that exists between body size and hemocyte number, and suggests that insulin-like signalling contributes to, but is not solely responsible for, keeping these tightly aligned during larval development.

genetics↗