In our lab we are studying how cell communicate and how changes in their metabolic pathways influence the behavior of neighboring cells. Using the power of Drosophila genetics and the high flexibility and availability of genetic tools, we are using animals carrying model of human diseases including tumors, neuronal degeneration and of metabolic disorders to analyze how changes in their metabolism may influence growth and survival.
The role of Myc on growth and in tumor: cell competition
Developing tumors are subjected to nutrient limitations, thus tumor cells reprogram their metabolic pathways to allow a better grow. One of the genes that control these mechanisms is the proto-oncogene c-myc. Expression of Myc activates survival pathways, including autophagy, a self eating process induced when nutrients are reduced, and cell-competition, a process described first for ribosomal proteins, that occurs when cells that are metabolically better fit or “winner” grow near wild-type “loser” cells with lower levels of Myc. These winner cells acquire a super-competitor condition and the ability to induce the death of the slower-growing cells. A similar event is described during the initial steps of cancerization when tumor-promoting genes in precancerous cells give a growth advantaged to the cells causing them to act as winners and to eliminate non-cancerous cells (losers). With genomics and proteomics approaches we found novel members of the ribosomal machinery and of lipid metabolism that we are currently characterizing for their role in myc-induced cell competition.
The role of Myc in tumors of the gut
Drosophila adult adult midgut is a well-established model to study the mechanisms responsible for differentiation and proliferation of the intestinal stem cell-niche as well as to study the relationship between the microbiome and stress related diseases causing inflammation and tumor progression. We previously underpinned pathways that control Myc protein stability; in addition we identify components of the deubiquitinase machinery responsible for controlling Myc expression and proliferation of the gut stem cells. Our aim is to characterize their role in controlling Myc activity.
The pathogenesis of many neuronal degeneration (NDD) diseases is mediated by metabolic changes, including increase in glutamate, mitochondria dysfunction resulting in cell death
Excess of glutamate is maintained at physiological level by a non-autonomous cycle between glia and neurons called “glutamate-glutamine cycle”. Glutamate removal from the synaptic cleft by glial cells is reduced in a model and patients with NDD, suggesting that glia cells actively participate in the survival of neurons. But how the glutamate-glutamine cycle contributes to the mechanisms of neuronal death? And which are the signaling molecules responsible for the cross talk between neurons and glial cells leading to neuronal survival? To answer these questions we manipulate, in neurons or glia, the expression of the key enzymes that control the “glutamate-glutamine” cycle in Drosophila models that have been successfully employed t o dissect the cellular and molecular events in polyglutamine-related diseases like Huntington’s Disease (HD), Spinocerebellar Ataxias (SCAs) and Amyotrophic Lateral sclerosis (ALS). Our preliminary data suggest a key function for GS1 and GDH in ameliorating animal motility and neuronal loss in a Drosophila model for HD resulting in the activation of autophagy, a self-cleaning process fundamental for neuronal survival.
In obese people the recruitment of immune cells (macrophages) to adipose tissue (Adipocyte Tissue Macrophages, ATMs) induces a low-grade of chronic inflammation
This status has been also linked to altered adipocyte metabolic function and to perturbations in lipid metabolism. To study the mechanisms that control chronic inflammation, we are taking advantage the conserved functional relationship in Drosophila between the immune cells, called hemocytes (macrophage like cells) and the larval fat body (which as similar function of the liver and adipose tissue). Using different model for obesity, we are currently studying the relevance of the classic cytokines pathways to ATM, as well as intervene using bioactive food like polyphenolic compounds, derived from fruits and vegetables, which we found to exert a strong protective action against obesity and adipose inflammation.
- Paola Bellosta, PI
- Francesca Destefanis, PhD student
- Valeria Manara, pre-doc
- Chiara Londero, pre-doc
- Stefania Santarelli, MA student
- Carlotta Candelaresi, MA student
- Marco Radoani, student
- Paola Maragno, student
Positions are available for motivated Master and PhD students, please contact the PI.
- Franco Taroni Neurological Institute “C. Besta” Milan, IT.
Genetic mechanism of Huntington Disease in human cells
- Alessandro Provenzani, CIBIO, University of Trento, IT.
Understanding the signaling of RAN translation using genetic interaction in Drosophila C9orf72/ALS model
- Gabriella Viero Fondazione Bruno Keller, Trento, IT.
Mechanism of ribosomal control in a Drosophila model for SMA (smn mutations)
- Maria A. Vanoni University of Milan, Italy.
Biochemical characterization of the enzymes controlling glutamate metabolism
- Adam Bajar University of South Boemia, Ceske Budejovice, Czech Republic.
Interaction between fat and macrophages or hemocytes in Drosophila
- Fulvio Mattivi, Dept of Chemistry, C3A, University of Trento, TN, Italy.
Isolation of antioxidants form plants and metabolomic analysis
- Ann Marie Schmidt at NYU Langone Medical Center New York, NY, USA.
Genetic modeling the expression of RAGE in obesity using flies
- Daniela Grifoni Cancer Modeling lab, University of Bologna, Italy.
Cell competition in Drosophila tumors
- Esteban Tabak, at Courant Mathematics Institute, NYU, New York, USA.
Mathematical modeling applied to growth and cell division
- Laura Johnston at Columbia University, New York, USA. Cell competition in Drosophila epithelial cells
Nucleolar NOC1 controls protein synthesis and cell competition in Drosophila. Destefanis F, Manara V, Santarelli S, Zola S, Brambilla M, Viola G, Maragno P, Viero G, Pasini ME, Penzo M and Bellosta P. 2021 biorXiv https://doi.org/10.1101/2021.07.06.451100
Myc as a Regulator of Ribosome Biogenesis and Cell Competition: A Link to Cancer. Destefanis F, Manara V, Bellosta P. Review Int J Mol Sci. 2020 Jun 5;21(11).
Glutamine Synthetase 1 Increases Autophagy Lysosomal Degradation of Mutant Huntingtin Aggregates in Neurons, Ameliorating Motility in a Drosophila Model for Huntington's Disease. Vernizzi L, Paiardi C, Licata G, Vitali T, Santarelli S, Raneli M, Manelli V, Rizzetto M, Gioria M, Pasini ME, Grifoni D, Vanoni MA, Gellera C, Taroni F, Bellosta P. Cells. 2020 Jan 13;9(1):196.
Drosophila melanogaster, Dissecting the Genetics of Autism Spectrum Disorders: A Drosophila Perspective. Bellosta P*, Soldano A*. Review Front Physiol. 2019 Aug 7;1 *corr author.
Drosophila melanogaster as a model organism to study cancer growth. Mirzoyan Z, Allocca MT, Valenza MA, Sollazzo M, Grifoni D, and Bellosta P. Review Frontiers in Genetics. 2019 Mar 1;10:51.
Anti-inflammatory effect of anthocyanins in a Drosophila model of chronic inflammation. Valenza A, Bonfanti C, Pasini MA, Bellosta P., Biomed Res Int. 2018 Mar 12;2018.
Human Cancer Cells Signal Their Competitive Fitness Through MYC Activity. Di Giacomo S, Sollazzo M, de Biase D, Ragazzi M, Bellosta P, Pession A, Grifoni D., Sci Rep. 2017 Oct 3;7(1):12568.
Modeling of Human Diseases using The Fruit Fly, Drosophila Melanogaster. Allocca MT, Zola S, Bellosta P, Drosophila melanogaster - Model for Recent Advances in Genetics and Therapeutics 2017 InTech Open ISBN 978-953-51-5484-6.
The Stearoyl-CoA Desaturase-1 (Desat1) in Drosophila cooperates with Myc to Induce Autophagy and Growth, a Potential New Link to Tumor Survival. Paiardi C, Mirzoyan Z, Zola S, Parisi F, Vingiani A, Pasini ME, Bellosta P. Genes (Basel). 2017 Apr 28;8(5).
Super-competitor status of Drosophila Myc cells requires p53 as a fitness sensor to reprogram metabolism and promote viability. de la Cova C, Senoo-Matsuda N, Ziosi M, Wu C, Bellosta P Quinzii CM and Johnston L. Cell Metabolism 2014 19(3):470-83.
dMyc expression in the fat body affects DILP2 release and increases the expression of the fat desaturase Desat1 resulting in organismal growth. Parisi F, Riccardo S, Zola S, Lora C, Grifoni D, Brown L and Bellosta P. Dev Biol. 2013 379(1):64-75 selected for F1000Prime.
Drosophila insulin and target of rapamycin (TOR) pathways regulate GSK3 beta activity to control Myc stability and determine Myc expression in vivo. Parisi F, Riccardo S, Daniel M, Saqcena M, Kundu N, Pession A, Grifoni D, Stocker H, Tabak E, Bellosta P. BMC Biol. 2011 Sep 27;9:65.
dMyc functions downstream of Yorkie to promote the supercompetitive behavior of hippo pathway mutant cells. Ziosi M, Baena-López LA, Grifoni D, Froldi F, Pession A, Garoia F, Trotta V, Bellosta P, Cavicchi S, Pession A. PLoS Genet. 2010 Sep 23;6(9).
The lethal giant larvae tumour suppressor mutation requires dMyc oncoprotein to promote clonal malignancy. Froldi F, Ziosi M, Garoia F, Pession A, Grzeschik NA, Bellosta P, Strand D, Richardson HE, Pession A, Grifoni D. BMC Biol. 2010 Apr 7;8:33.
Identification of domains responsible for ubiquitin-dependent degradation of dMyc by glycogen synthase kinase 3beta and casein kinase 1 kinases. Galletti M, Riccardo S, Parisi F, Lora C, Saqcena MK, Rivas L, Wong B, Serra A, Serras F, Grifoni D, Pelicci P, Jiang J, Bellosta P. Mol Cell Biol. 2009 Jun;29(12):3424-34. Cover
Myc interacts genetically with Tip48/Reptin and Tip49/Pontin to control growth and proliferation during Drosophila development. Bellosta P, Hulf T, Balla Diop S, Usseglio F, Pradel J, Aragnol D, Gallant P. Proc Natl Acad Sci U S A. 2005 Aug 16;102(33):11799-804.
Drosophila myc regulates organ size by inducing cell competition. de la Cova C, Abril M, Bellosta P, Gallant P, Johnston LA. Cell. 2004 Apr 2;117(1):107-16. Cover
Please see www.paolabellosta.com for a complete list of publications with links to pdf files.