Cell Signalling Architecture team

@DTU Bioengineering and @University of Manchester

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Team interests

We aim at uncovering the molecular mechanisms underlying signalling architecture and cellular outputs in different model systems (breast cancer and skin models in two- and three-dimensions, co-culture, PDXs, patient samples).

We focus on how:

* the cellular microenvironment affects signalling architecture and cell survival

* trafficking of receptor tyrosine kinases (RTKs) from and to the plasma membrane regulates the balance between cell proliferation, motility, and survival

* functional selectivity determines cell fate

We integrate quantitative mass-spectrometry-based (phospho) proteomics and metabolomics, bioinformatics analysis, mathematical modelling, AI, functional assays, and advanced imaging techniques.

We collaborate with experts in omics, cell signalling, and bioinformatics nationally and internationally and we are very active in the signalling and omics communities.

The final goal is to identify and characterize proteins with key roles in cellular signalling and cell survival which can be targeted for personalized intervention in human diseases.

Workflow used by the Francavilla_team

Team Publications

Tulika T., et al., Francavilla C., Schlothauer T., Lomonte B., Andersen J.T., Laustsen A.H.Engineering of pH-dependent antigen binding properties for toxin-targeting IgG1 antibodies using light-chain shuffling.(2024).Structure.Aug 12:S0969-2126(24)00277-6. doi: 10.1016/j.str.2024.07.014.

Madzharova E.,* Sabino F., Kalogeropoulos K., Francavilla C.*, Auf dem Keller U.Substrate O-glycosylation actively regulates extracellular proteolysis.(2024).Protein Sci .Aug;33(8):e5128. doi: 10.1002/pro.5128.

Samad S.S., Schwartz J.M.*, Francavilla C.*Functional selectivity of Receptor Tyrosine Kinases regulates distinct cellular outputs.(2024).Front Cell Dev Biol .Jan 8:11:1348056. doi: 10.3389/fcell.2023.1348056.

Francavilla C.*Surviving under stress conditions.(2023). Nat Struct Mol Biol .Nov;30(11):1609-1611. doi: 10.1038/s41594-023-01116-2.

Veth T.S., Francavilla C., Heck A.J.R., Altelaar M.Elucidating Fibroblast Growth Factor-induced kinome dynamics using targeted mass spectrometry and dynamic modeling.(2023).Mol Cell Proteomics.Jun 14:100594. doi: 10.1016/j.mcpro.2023.100594.

Ogden S., Ahmed I., Yang S.H., Fullwood P.; OCCAMS consortium; Francavilla C.*, Sharrocks A.D.*Oncogenic ERRB2 signals through the AP-1 transcription factor to control mesenchymal-like properties of oesophageal adenocarcinoma.(2023).NAR Cancer.Jan 23;5(1):zcad001. doi: 10.1093/narcan/zcad001. eCollection 2023 Mar.

Watson J., Ferguson R.H., Brady R.M., Ferguson J., Fullwood P., Mo H., Bexley K.H., Knight D., Howell G., Schwartz J-M., Smith M.P.*, Francavilla C.* Spatially resolved phosphoproteomics reveals fibroblast growth factor receptor recycling-driven regulation of autophagy and survival.(2022).Nat Commun.Nov 3;13(1):6589. doi: 10.1038/s41467-022-34298-2.

Wilcock D.J., Badrock A.P., Wong C.W., Owen R., Guerin M., Southam A.D., Johnston H., Telfer B.A., Fullwood P., Watson J., Ferguson H., Ferguson J., Lloyd G.R., Jankevics A., Dunn W.B., Wellbrock C., Lorigan P., Ceol C., Francavilla C.*, Smith M.P.*, Hurlstone A.F.L.* Oxidative stress from DGAT1 oncoprotein inhibition in melanoma suppresses tumor growth when ROS defenses are also breached.(2022).Cell Rep.Jun 21;39(12):110995. doi: 10.1016/j.celrep.2022.110995.

Mo H., Breitling R*., Francavilla C.*, Schwartz J.M*. Data integration and mechanistic modelling for breast cancer biology: Current state and future directions.(2022).Curr Opin Endocr Metab Res.Jun;24:None. doi: 10.1016/j.coemr.2022.100350. PMID: 36034741.

Watson J., Smith M., Francavilla C.*, Schwartz J.M..SubcellulaRVis: a web-based tool to simplify and visualise subcellular compartment enrichment.(2022).Nucleic Acids Res.May 10;50(W1):W718-25. doi: 10.1093/nar/gkac336.

Francavilla C.* and O'Brien C.Fibroblast growth factor receptor signalling dysregulation and targeting in breast cancer.(2022).Open Biology.Feb;12(2):210373. doi: 10.1098/rsob.210373. Epub 2022 Feb 23.

Watson J., Schwartz J.M., Francavilla C.* Using Multilayer Heterogeneous Networks to Infer Functions of Phosphorylated Sites.(2021).J. Proteome Res.Jul 2;20(7):3532-3548. doi: 10.1021/acs.jproteome.1c00150. Epub 2021 Jun 24.

Smith M.P., Ferguson H.R., Ferguson J., Zindy E., Kowalczyk K.M., Kedward T., Bates C., Parsons J., Watson J., Chandler S., Fullwood P., Warwood S., Knight D., Clarke R.B., Francavilla C.* Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs.(2021).The EMBO Journal.Jun 4:e107182. doi: 10.15252/embj.2020107182.

Ferguson H.R., Smith M.P.*, Francavilla C.* Fibroblast Growth Factor Receptors (FGFRs) and Noncanonical Partners in Cancer Signaling.(2021).Cells.May 14;10(5):1201. doi: 10.3390/cells10051201.

Pedersen A.K., Pfeiffer A., Karemore G., Akimov V., Bekker-Jensen D.B., Blagoev B., Francavilla C.*#, Olsen J.V.#. #, equal senior contribution Proteomic investigation of Cbl and Cbl-b in neuroblastoma cell differentiation highlights roles for SHP-2 and CDK16.(2021).iScience..Mar 17;24(4):102321. doi: 10.1016/j.isci.2021.102321. eCollection 2021 Apr 23. PMID: 33889818.

Parsons J., Francavilla C.*'Omics Approaches to Explore the Breast Cancer Landscape.(2020).Front Cell Dev Biol..Jan 22;7:395. doi: 10.3389/fcell.2019.00395. eCollection 2019. Review.

Pearson A. J., Fullwood P., Toro Tapia G., Prise I., Smith M.P., Xu Q., Jordan A., Giurisato E., Whitmarsh A.J., Francavilla C., Tournier C..Discovery of a Gatekeeper Residue in the C-Terminal Tail of the Extracellular Signal-Regulated Protein Kinase 5 (ERK5).(2020).Int J Mol Sci. .Jan 31;21(3). pii: E929. doi: 10.3390/ijms21030929.

Hamilton W. B., Mosesson Y., Monteiro R.S., Emdal K. B., Knudsen T.E., Francavilla C., Barkai N., Olsen J.V., Brickman J.M..Dynamic lineage priming is driven via direct enhancer regulation by ERK.(2019).Nature.Nov;575(7782):355-360. doi: 10.1038/s41586-019-1732-z. Epub 2019 Nov 6.

Lundby A., Franciosa G., Emdal K.B., Refsgaard J.C., Gnosa S. P., Bekker-Jensen D.B., Secher A., Maurya S. R., Paul I., Mendez B.I., Kelstrup C.D., Francavilla C., Kveilborg M., Montoya G., Jensen L.J., Olsen J.V..Oncogenic mutations rewire signaling pathways by switching protein recruitment to phosphotyrosine sites .(2019).Cell.Oct 3;179(2):543-560.e26. doi: 10.1016/j.cell.2019.09.008.

Zamai M., Trullo A., Giordano M., Corti V., Cuesta E. A., Francavilla C., Cavallaro U., Caiolfa V. R..Number and brightness analysis in live cells reveals that NCAM and FGF2 elicit different assembly and dynamics of FGFR1.(2019).J Cell Sci .Jan 3;132(1). pii: jcs220624. doi: 10.1242/jcs.220624.

Emdal K. B., Pedersen A. K., Bekker-Jensen D. B., Lundby A., Claeys S., De Preter K., Speleman F., Francavilla C.*#, Olsen J. V.*#. #, equal senior contributionIntegrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma.(2018).Sci Signal.Nov 20;11(557).

Watson J., Francavilla C.*Regulation of FGF10 Signaling in Development and Disease.(2018).Front Genet.Oct 23;9:500.

Batth T.S., Papetti M., Pfeiffer A., Tollenaere M.A.X., Francavilla C.*, and Olsen J.V.*.Large-scale phosphoproteomics reveals Shp2 phosphatase-dependent regulators of Pdgf receptor signaling.(2018).Cell Rep.Mar 6;22(10):2784-2796.

Sanchez-Quiles V., Akimov V., Osinalde N., Francavilla C., Puglia M., Barrio-Hernandez I., Kratchmarova I., Olsen J.V., Blagoev B..Cylindromatosis Tumor Suppressor Protein (CYLD) Deubiquitinase is Necessary for Proper Ubiquitination and Degradation of the Epidermal Growth Factor Receptor.(2017).Mol Cell Proteomics. Aug;16(8):1433-1446.

Francavilla C.*, Lupia M., Tsafou K., Villa A., Kowalczyk K., Rakownikow Jersie-Christensen R., Bertalot G., Confalonieri S., Brunak S., Jensen L.J., Cavallaro U.*, Olsen J.V.*.Phosphoproteomics of Primary Cells Reveals Druggable Kinase Signatures in Ovarian Cancer.(2017).Cell Rep. Mar 28;18(13):3242-3256.

Francavilla C.*, Papetti M., Rigbolt T.G., Pedersen A-K., Sirurdson J.O., Cazzamali G., Karemore G., Blagoev B., Olsen J.V.*.Multi-layered Proteomics reveals Molecular Switches Dictating Ligand-dependent EGFR Trafficking.(2016).Nat. Struct. Mol. Biol. 23(6):608-18.

Von Stechow L., Francavilla C., Olsen J.V.Recent findings and technological advances in phopshoproteomics for cells and tissues.(2015).Expert. Rev. Proteomics.12(5): 469-487.

Satpathy S., Wagner S.A., Beli P., Gupta R., Kristiansen T.A., Malinova D., Francavilla C., Tolar P., Bishop G.A., Hostager B.S., Choudhary C Systems-wide analysis of BCR signalosomes and downstream phosphorylation and ubiquitylation.(2015).Molecular systems biology.11(6): 810 (Highlighted in the Editors' Choice section of Science Signaling: B cell receptor signaling dynamics, Sudhakaran Prabakaran, (2015) Sci Signal. 8, Issue 384, pp. ec186).

Emdal K.B., Pedersen A.K., Bekker-Jensen D.B., Tsafou K.P., Horn H., Lindner S., Schulte J.H., Eggert A., Jensen L.J., Francavilla C.*#, Olsen J.V.*#.#, equal senior contributionTemporal proteomics of NGF-TrkA signaling identifies an inhibitory role for the E3 ligase Cbl-b in neuroblastoma cell differentiation.(2015).Science signaling. 8(374): ra40 (Featured with the cover image).

Batth T.S., Francavilla C., Olsen J.VOff-line high-pH reversed-phase fractionation for in-depth phosphoproteomics.(2014).Journal of proteome research.Dec 5, 13(12): 6176-86.

Francavilla C., Hekmat O., Blagoev B., Olsen J.VSILAC-based temporal phosphoproteomics.(2014).Methods Mol Biol.Jul, 1188: 125-48.

Schimmel J., Eifler K., Sigurethsson J.O., Cuijpers S.A., Hendriks I.A., Verlaan-de Vries M., Kelstrup C.D., Francavilla C., Medema R.H., Olsen J.V., Vertegaal A.C.Uncovering SUMOylation dynamics during cell-cycle progression reveals FoxM1 as a key mitotic SUMO target protein.(2014).Molecular cell..Mar 20, 53(6): 1053-66.

Petersen D.L., Krejsgaard T., Berthelsen J., Fredholm S., Willerslev-Olsen A., Sibbesen N.A., Bonefeld C.M., Andersen M.H., Francavilla C., Olsen J.V., Hu T., Zhang M., Wasik M.A., Geisler C., Woetmann A., Odum N. B-lymphoid tyrosine kinase (Blk) is an oncogene and a potential target for therapy with dasatinib in cutaneous T-cell lymphoma (CTCL).(2014).Leukemia.Oct, 28(10): 2109-12.

Radhakrishnan P., Dabelsteen S., Madsen F.B., Francavilla C., Kopp K.L., Steentoft C., Vakhrushev S.Y., Olsen J.V., Hansen L., Bennett E.P., Woetmann A., Yin G., Chen L., Song H., Bak M., Hlady R.A., Peters S.L., Opavsky R., Thode C., Qvortrup K., Schjoldager K.T., Clausen H., Hollingsworth M.A., Wandall H.H. Immature truncated O-glycophenotype of cancer directly induces oncogenic features.(2014).Proceedings of the National Academy of Sciences of the United States of America.Sep 30, 111(39): E4066-75.

Lundby A., Andersen M.N., Steffensen A.B., Horn H., Kelstrup C.D., Francavilla C., Jensen L.J., Schmitt N., Thomsen M.B., Olsen J.V. In vivo phosphoproteomics analysis reveals the cardiac targets of beta-adrenergic receptor signaling.(2013).Science signaling.Jun 4, 6(278): rs11.

Galli G.G., Carrara M., Francavilla C., de Lichtenberg K.H., Olsen J.V., Calogero R.A., Lund A.H. Genomic and proteomic analyses of Prdm5 reveal interactions with insulator binding proteins in embryonic stem cells.(2013).Molecular and cellular biology.Nov, 33(22): 4504-16.

Hekmat O., Munk S., Fogh L., Yadav R., Francavilla C., Horn H., Wurtz S.O., Schrohl A.S., Damsgaard B., Romer M.U., Belling K.C., Jensen N.F., Gromova I., Bekker-Jensen D.B., Moreira J.M., Jensen L.J., Gupta R., Lademann U., Brunner N., Olsen J.V., Stenvang J. TIMP-1 increases expression and phosphorylation of proteins associated with drug resistance in breast cancer cells.(2013).Journal of proteome research.Sep 6, 12(9): 4136-51..

Francavilla C., Rigbolt K.T., Emdal K.B., Carraro G., Vernet E., Bekker-Jensen D.B., Streicher W., Wikstrom M., Sundstrom M., Bellusci S., Cavallaro U., Blagoev B., Olsen J.V.Functional proteomics defines the molecular switch underlying FGF receptor trafficking and cellular outputs..(2013).Molecular cell.Sep 26, 51(6): 707-22 (Highlighted in the Editors' Choice section of Science Signaling: Dictating the Route, Nancy R. Gough, (2013) Sci Signal. 6, Issue 295, pp. ec236).

Kelstrup C.D., Hekmat O., Francavilla C., Olsen J.V. Pinpointing phosphorylation sites: Quantitative filtering and a novel site-specific x-ion fragment.(2011).Journal of proteome research.Jul 1, 10(7): 2937-48.

Murakami M., Francavilla C., Torselli I., Corada M., Maddaluno L., Sica A., Matteoli G., Iliev I.D., Mantovani A., Rescigno M., Cavallaro U., Dejana E. nactivation of junctional adhesion molecule-A enhances antitumoral immune response by promoting dendritic cell and T lymphocyte infiltration.(2010).Cancer research.Mar 1, 70(5): 1759-65.

Monegal A., Ami D., Martinelli C., Huang H., Aliprandi M., Capasso P., Francavilla C., Ossolengo G., de Marco A. Immunological applications of single-domain llama recombinant antibodies isolated from a naive library.(2009).Protein engineering, design & selection : PEDS.Apr, 22(4): 273-80.

Francavilla C., Cattaneo P., Berezin V., Bock E., Ami D., de Marco A., Christofori G., Cavallaro U. The binding of NCAM to FGFR1 induces a specific cellular response mediated by receptor trafficking.(2009).The Journal of cell biology.Dec 28, 187(7): 1101-16.

Francavilla C.#, Maddaluno L.#, Cavallaro U. #, equal contribution The functional role of cell adhesion molecules in tumor angiogenesis..(2009).Seminars in cancer biology..Oct, 19(5): 298-309.

Francavilla C., Loeffler S., Piccini D., Kren A., Christofori G., Cavallaro U. Neural cell adhesion molecule regulates the cellular response to fibroblast growth factor.(2007).Journal of cell science.Dec 15, 120(Pt 24): 4388-94.

* corresponding author

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