Maria Genander

Ragnar Söderbergforskare i medicin // År: 2015 //
Anslagsförvaltare: Karolinska Institutet // Belopp: 8 000 000 kr

Huden som modellsystem för normal vävnad och cancer

En människa drabbas av cancer när de processer som begränsar kroppens celldelning havererar. Maria Genander jämför proteiner i sjuka hudceller med samma proteiner i normala hudceller, för att öka förståelsen av förloppet. På sikt vill hon bidra till nya strategier för behandling av hudcancerpatienter.

Stamceller har till uppgift att generera alla typer av specialiserade celler i ett organ. Hudens stamceller gör till exempel så att huden kontinuerligt kan skapa nya hudceller och läka skador.

Cancer uppstår när de processer som reglerar och begränsar celldelning havererar. Det har dock visat sig att det finns stora likheter mellan dessa processer och hur normala stamceller styrs. Genom att studera en familj av proteiner som finns i både normala stamceller och tumörceller i huden vill Maria Genander kartlägga detta samband ytterligare.

Forskningsprojektet kommer att öka förståelsen för hur normala stamceller ersätter förlorade celler i huden – och hur mekanismen utnyttjas och förändras i cancerstamceller. Målet är att hitta nya strategier för behandling av hudcancer.

Research

Stem cells are defined by the properties of self-renewal and multipotency. Recently, tumor cells have been identified which have the capacity to initiate tumors and recapitulate the lineage heterogeneity of the parental tumor, thus displaying characteristics of (cancer) stem cells. Targeting of these rare cancer stem cells is a prerequisite for any curative therapeutic treatment. 

Inhibitors of DNA binding (ID) proteins are master regulators of diverse stem cell phenotypes, which collectively create the stem cell state - both in tissue and transformed stem cells rendering this family of dominant negative bHLH transcription factors ideal candidates to understand the link between homeostasis and tumor development. 

Current knowledge of ID proteins as key stem cell factors comes mainly from loss-of-function studies, however the downstream mechanisms are still lacking. This proposal will for the first time provide a map of the transcriptional network directly influenced by ID proteins. By combining in vivo manipulation of gene expression and ChIP-sequencing with transcriptional profiling in both tissue and transformed stem cells, this project will be able to address hitherto outstanding questions of epidermal transcriptional regulatory networks and their implication for tissue homeostasis and cancer initiation. Furthermore, candidates suited for pharmacological targeting are likely to be identified as genome wide bHLH sensitive targets are mapped and functionally characterized.

Publikationer i urval

Kundu P* , Genander M* , Strååt K, Classon J, Ridgway RA, Tan EH, Björk J, Martling A, van Es J, Sansom OJ, Clevers H, Pettersson S and Frisén J An EphB-Abl signaling pathway important for intestinal tumor initiation and growth Science Translational Medicine (2015) Apr 1;7(281):281ra44 PMID: 25834110

Genander M, Cook PJ, Ramsköld D, Keyes BE, Mertz AF, Sandberg R, Fuchs E BMP signaling and its pSMAD1/5 target genes differentially regulate hair follicle stem cell lineages Cell Stem Cell (2014) Nov 6;15(5):619-633 PMID: 25312496

Kadaja M, Keyes BE, Lin M, Pasolli HA, Genander M, Polak L, Stokes N, Zheng D, Fuchs E SOX9: a stem cell transcriptional regulator of secreted niche signaling factors Genes and Development (2014) Feb 15:28(4)328-41 PMID:24532713

Genander M Eph and ephrins in epithelial stem cell niches and cancer Cell Adh Migr. (2012) Mar-Apr;6(2):126-30 PMID: 22568955

Genander M, Holmberg J, Frisén J Ephrins negatively regulate proliferation in the epidermis and hair follicle Stem Cells (2010) May 10 PMID: 20506314

Genander M, Frisén J Ephrins and Eph receptors in stem cells and cancer Current Opinion in Cell Biology (2010) 22:1-6 PMID: 20810264

Genander M, Frisén J Eph receptors tangled up in two: independent control of cell positioning and proliferation Cell Cycle (2010) May 3;9(10) PMID: 20436281

Genander M, Halford MM, Xu N, Eriksson M, Xu Z, Qiu Z, Martling A, Greicius G, Thakar S, Catchpole T, Chumley MJ, Zdunek S, Wang C, Holm T, Goff SP, Petterson S, Pestell RG, Henkemeyer M, Frisén J Dissociation of EphB signaling pathways mediating progenitor cell proliferation and tumor suppression Cell (2009) Nov 13;139(4):679-692 PMID: 19914164

Månsson-Broberg A, Siddiqui AJ, Genander M, Grinnemo KH, Hao X, Andersson AB, Wärdell E, Sylvén C, Corbascio M Modulation of ephrinB2 leads to increased angiogenesis in ischemic myocardium and endothelial cell proliferation Biochem Biophys Res Commun (2008) Aug 29:373(3):335-9 PMID: 18571496

Holmberg J* , Genander M*, Halford MM, Annerén C, Sondell M, Chumley MJ, Silvany RE, Henkemeyer M, Frisén J EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell (2006) Jun 16;125(6):1151-63 PMID: 16777604

*equal contribution