Chris Madsen

Ragnar Söderbergforskare i medicin // År: 2015 //
Anslagsförvaltare: Lunds universitet // Belopp: 8 000 000 kr

Min forskning

Cancercellens rörelse i frisk och sjuk vävnad

Många dödsfall i cancer beror på att sjukdomen sprider sig till andra organ än det ursprungliga. Genom att förändra sitt rörelsemönster lyckas cancerceller anpassa sig till den angripna kroppen. Chris Madsens forskning går ut på att kartlägga hur cellerna rör sig i både frisk och sjuk vävnad.

Metastaser – när cancer sprider sig till andra organ än det ursprungliga – orsakar 90 procent av alla dödsfall i sjukdomen. För att kunna sprida sig måste cancercellerna förändra sitt rörelsemönster, för att anpassa sig till vävnaderna i olika delar av kroppen.

Chris Madsen studerar ett nyupptäckt proteinkomplex, STRIPAK, som har stor betydelse för cellernas föränderliga rörelsemönster. Komplexet är inte bara betydelsefullt för cancer, utan även i embryonalutveckling. Det verkar därför som att cancercellerna ”kidnappar” en utvecklingsbiologisk process för att kunna sprida sig. Målet är att ta reda på hur cancerceller rör sig i frisk och sjuk vävnad. Utifrån det kommer Chris Madsens forskargrupp även utveckla ett test som kan användas för att bestämma hur aggressiv behandling en cancerpatient behöver.

 

Research

Metastasis is responsible for ~90% of cancer patient deaths. In order for cancer cells to spread, they need to adapt to the tissue environment they encounter. On their journey they will meet obstacles of various physical properties (rigidity, confinement, adhesion and topology), and the cells have therefore developed strategies to circumvent these challenges, a term known as ‘plasticity of cell migration’. We recently discovered that the STRIPAK complex is an important and ancient regulator of ‘plasticity of cell migration’ in both developmental processes and cancer metastasis; we believe that we have discovered a novel developmental mechanism hijacked by the tumour cells.

We will use high resolution imaging and intravital imaging to understand how the STRIPAK complex is regulating cancer cell migration through tissue. We will also substantiate the prognostic values of perturbed and mutated STRIPAK component in cancer patients. The aim is to push this discovery, and to determine if this can be turned into a prognostic test that might inform how aggressively the cancer disease should be treated. 

Activation of cancer-associated fibroblasts (CAFs) is another detrimental regulator of the environment. CAFs promote cancer progression and cancer cell dissemination. We have only just discovered that CAF activation can be reverted towards a quiescence state. We will attempt to determine the epigenetic changes and the coexisting mechanisms taking place in CAFs during cancer evolution.

Publikationer i urval

Madsen CD, Hooper S, Tozluoglu M, Bruckbauer A, , Fletcher G, Erler JT, Bates PA, Thompson B, Sahai E. STRIPAK components determine mode of cancer cell migration and metastasis. Nature Cell Biology. 2015 Jan;17(1):68-80.

Ferraris GM, Schulte C, Buttiglione V, De Lorenzi V, Piontini A, Galluzzi M, Podestà A, Madsen CD, Sidenius N. The interaction between uPAR and vitronectin triggers ligand-independent adhesion signalling by integrins. EMBO J. 2014 Nov 3;33(21):2458-72.

Linch M, Sanz-Garcia M, Rosse C, Riou P, Peel N, Madsen C, Sahai E, Downward J, Khwaja A, Dillon C, Roffey, J, Cameron A, Parker PJ. Regulation of polarized morphogenesis by protein kinase C iota in oncogenic epithelial spheroids. Carcinogenesis, 2013, Sept 26

Pellegrino L, Stebbing J, Braga VM, Frampton AE, Jacob J, Buluwela L, Jiao LR, Periyasamy M, Madsen CD, Caley MP, Ottaviani S, Roca-Alonso L, El-Bahrawy M, Coombes RC, Krell J, Castellano L. miR-23b regulates cytoskeletal remodeling, motility and metastasis by directly targeting multiple transcripts. Nucleic Acid Research, 2013, April 10.

Briones-Orta MA, Levy L, Madsen CD, Das D, Erker Y, Sahai E, Hill CS. Arkadia regulates tumor metastasis by modulation of the TGF-β pathway. Cancer Research, 2013, Mar 15; 73(16):1800- 10.

Madsen CD, Sahai E. Cancer Dissemination—Lessons from Leukocytes; Developmental Cell, 2010, 19 (1): 13-26.

Cortese K, Sahores M, Madsen CD, Tacchetti C, Blasi F. Clathrin and LRP-1-independent constitutive endocytosis and recycling of uPAR. PLoS One, 2008;3 (11): e3730. Curriculum Vitae Dr. Chris D. Madsen 3

Madsen CD*, Sidenius N. The interaction between urokinase receptor and vitronectin in cell adhesion and signalling. European Journal of Cell Biology; 2008, 87: 617–629. 

Caiolfa VR, Zamai M, Malengo G, Andolfo A, Madsen CD, Sutin J, Digman M, Gratton E, Blasi F, Sidenius N. Monomer-dimer dynamics and distribution of GPI-anchored uPAR are determined by cell surface protein assemblies. Journal of Cell Biology, 2007; 179 (5), 1067-1082.

Madsen CD, Sarra Ferraris GM, Andolfo A, Cunningham O, Sidenius N. uPAR-induced cell adhesion and migration: Vitronectin provides the key. Journal of Cell Biology, 2007; 177 (5), 927-939.

* Corresponding author

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