TY - JOUR AB - Solute carriers are increasingly recognized as participating in a plethora of pathologies, including cancer. We describe here the involvement of the orphan solute carrier MFSD1 in the regulation of tumor cell migration. Loss of MFSD1 enabled higher levels of metastasis in a mouse model. We identified an increased migratory potential in MFSD1-/- tumor cells which was mediated by increased focal adhesion turn-over, reduced stability of mature inactive β1 integrin, and the resulting increased integrin activation index. We show that MFSD1 promoted recycling to the cell surface of endocytosed inactive β1 integrin and thereby protected β1 integrin from proteolytic degradation; this led to dampening of the integrin activation index. Furthermore, down-regulation of MFSD1 expression was observed during early steps of tumorigenesis and higher MFSD1 expression levels correlate with a better cancer patient prognosis. In sum, we describe a requirement for endolysosomal MFSD1 in efficient β1 integrin recycling to suppress tumor spread. AU - Roblek, Marko AU - Bicher, Julia AU - van Gogh, Merel AU - György, Attila AU - Seeböck, Rita AU - Szulc, Bozena AU - Damme, Markus AU - Olczak, Mariusz AU - Borsig, Lubor AU - Siekhaus, Daria E ID - 10712 JF - Frontiers in Oncology SN - 2234-943X TI - The solute carrier MFSD1 decreases β1 integrin’s activation status and thus tumor metastasis VL - 12 ER - TY - JOUR AB - Cellular metabolism must adapt to changing demands to enable homeostasis. During immune responses or cancer metastasis, cells leading migration into challenging environments require an energy boost, but what controls this capacity is unclear. Here, we study a previously uncharacterized nuclear protein, Atossa (encoded by CG9005), which supports macrophage invasion into the germband of Drosophila by controlling cellular metabolism. First, nuclear Atossa increases mRNA levels of Porthos, a DEAD-box protein, and of two metabolic enzymes, lysine-α-ketoglutarate reductase (LKR/SDH) and NADPH glyoxylate reductase (GR/HPR), thus enhancing mitochondrial bioenergetics. Then Porthos supports ribosome assembly and thereby raises the translational efficiency of a subset of mRNAs, including those affecting mitochondrial functions, the electron transport chain, and metabolism. Mitochondrial respiration measurements, metabolomics, and live imaging indicate that Atossa and Porthos power up OxPhos and energy production to promote the forging of a path into tissues by leading macrophages. Since many crucial physiological responses require increases in mitochondrial energy output, this previously undescribed genetic program may modulate a wide range of cellular behaviors. AU - Emtenani, Shamsi AU - Martin, Elliot T AU - György, Attila AU - Bicher, Julia AU - Genger, Jakob-Wendelin AU - Köcher, Thomas AU - Akhmanova, Maria AU - Pereira Guarda, Mariana AU - Roblek, Marko AU - Bergthaler, Andreas AU - Hurd, Thomas R AU - Rangan, Prashanth AU - Siekhaus, Daria E ID - 10918 JF - The Embo Journal TI - Macrophage mitochondrial bioenergetics and tissue invasion are boosted by an Atossa-Porthos axis in Drosophila VL - 41 ER - TY - JOUR AB - Optogenetics has been harnessed to shed new mechanistic light on current and future therapeutic strategies. This has been to date achieved by the regulation of ion flow and electrical signals in neuronal cells and neural circuits that are known to be affected by disease. In contrast, the optogenetic delivery of trophic biochemical signals, which support cell survival and are implicated in degenerative disorders, has never been demonstrated in an animal model of disease. Here, we reengineered the human and Drosophila melanogaster REarranged during Transfection (hRET and dRET) receptors to be activated by light, creating one-component optogenetic tools termed Opto-hRET and Opto-dRET. Upon blue light stimulation, these receptors robustly induced the MAPK/ERK proliferative signaling pathway in cultured cells. In PINK1B9 flies that exhibit loss of PTEN-induced putative kinase 1 (PINK1), a kinase associated with familial Parkinson’s disease (PD), light activation of Opto-dRET suppressed mitochondrial defects, tissue degeneration and behavioral deficits. In human cells with PINK1 loss-of-function, mitochondrial fragmentation was rescued using Opto-dRET via the PI3K/NF-кB pathway. Our results demonstrate that a light-activated receptor can ameliorate disease hallmarks in a genetic model of PD. The optogenetic delivery of trophic signals is cell type-specific and reversible and thus has the potential to inspire novel strategies towards a spatio-temporal regulation of tissue repair. AU - Inglés Prieto, Álvaro AU - Furthmann, Nikolas AU - Crossman, Samuel H. AU - Tichy, Alexandra Madelaine AU - Hoyer, Nina AU - Petersen, Meike AU - Zheden, Vanessa AU - Bicher, Julia AU - Gschaider-Reichhart, Eva AU - György, Attila AU - Siekhaus, Daria E AU - Soba, Peter AU - Winklhofer, Konstanze F. AU - Janovjak, Harald L ID - 9363 IS - 4 JF - PLoS genetics TI - Optogenetic delivery of trophic signals in a genetic model of Parkinson's disease VL - 17 ER - TY - JOUR AB - Aberrant display of the truncated core1 O-glycan T-antigen is a common feature of human cancer cells that correlates with metastasis. Here we show that T-antigen in Drosophila melanogaster macrophages is involved in their developmentally programmed tissue invasion. Higher macrophage T-antigen levels require an atypical major facilitator superfamily (MFS) member that we named Minerva which enables macrophage dissemination and invasion. We characterize for the first time the T and Tn glycoform O-glycoproteome of the Drosophila melanogaster embryo, and determine that Minerva increases the presence of T-antigen on proteins in pathways previously linked to cancer, most strongly on the sulfhydryl oxidase Qsox1 which we show is required for macrophage tissue entry. Minerva’s vertebrate ortholog, MFSD1, rescues the minerva mutant’s migration and T-antigen glycosylation defects. We thus identify a key conserved regulator that orchestrates O-glycosylation on a protein subset to activate a program governing migration steps important for both development and cancer metastasis. AU - Valosková, Katarina AU - Biebl, Julia AU - Roblek, Marko AU - Emtenani, Shamsi AU - György, Attila AU - Misova, Michaela AU - Ratheesh, Aparna AU - Rodrigues, Patricia AU - Shkarina, Katerina AU - Larsen, Ida Signe Bohse AU - Vakhrushev, Sergey Y AU - Clausen, Henrik AU - Siekhaus, Daria E ID - 6187 JF - eLife SN - 2050-084X TI - A conserved major facilitator superfamily member orchestrates a subset of O-glycosylation to aid macrophage tissue invasion VL - 8 ER - TY - JOUR AB - Migrating cells penetrate tissue barriers during development, inflammatory responses, and tumor metastasis. We study if migration in vivo in such three-dimensionally confined environments requires changes in the mechanical properties of the surrounding cells using embryonic Drosophila melanogaster hemocytes, also called macrophages, as a model. We find that macrophage invasion into the germband through transient separation of the apposing ectoderm and mesoderm requires cell deformations and reductions in apical tension in the ectoderm. Interestingly, the genetic pathway governing these mechanical shifts acts downstream of the only known tumor necrosis factor superfamily member in Drosophila, Eiger, and its receptor, Grindelwald. Eiger-Grindelwald signaling reduces levels of active Myosin in the germband ectodermal cortex through the localization of a Crumbs complex component, Patj (Pals-1-associated tight junction protein). We therefore elucidate a distinct molecular pathway that controls tissue tension and demonstrate the importance of such regulation for invasive migration in vivo. AU - Ratheesh, Aparna AU - Biebl, Julia AU - Smutny, Michael AU - Veselá, Jana AU - Papusheva, Ekaterina AU - Krens, Gabriel AU - Kaufmann, Walter AU - György, Attila AU - Casano, Alessandra M AU - Siekhaus, Daria E ID - 308 IS - 3 JF - Developmental Cell TI - Drosophila TNF modulates tissue tension in the embryo to facilitate macrophage invasive migration VL - 45 ER -