Cáncer

“As incredible as it seems, future research on flies and worms will quite often provide the shortest and most efficient path to curing human disease” Bruce Alberts (Editor in Chief), Science 330, 1724 (2010) ¿ Puede ayudar Drosophila a entender el Cancer ?

The Genetics of Cancer The cancer genome Stratton et al Nature 458, (2009) “…with at least 350 (1.6%) of the approx 22,000 protein-coding genes in the human genome reported to show recurrent somatic mutations in cancer with strong evidence that these contribute to cancer development.” “The size of the full repertoire of human cancer genes is a matter of speculation. However, studies in mice have suggested that more than 2,000 genes, when appropriately altered, may have the potential to contribute to cancer development”

Signalling pathways: Hedgehog, Wnt, Dpp, JNK Insulin pathway: pten, tsc1, tsc2 Cell proliferation control: Hippo/salv/warts Endocytic pathway: avalanche, rab5, vps25 Apico-basal polarity: disc large (dlg), scribble (scrib), lethal giant larvae (lgl) Oncogenic mutations in Drosophila These genes are present in humans; mutations in the human homologues are also associated with tumours Drosophila Humans scribble hScrib disc large hDLG1 lethal giant larvae Hugl-1

lgl mutant larvae grow very large and develop extensive tumours lgl - wt lgl - Brain Wing disc wt

5 days disc wtlgl 4 7 days 8 days 11 days lgl mutant discs grow at normal rate but continue growing until the larva dies PH3 wildtype embryoLarval periodPupariationAdult life lgl - larvae Extended larval period Giant larva dies 5 days 4 days days embryo Mutant discs are unable to generate a stop-growth signal; a major tumorigenic feature

Normally tumours develop from isolated groups of cells that appear in normal individuals After Moreno 2007 Evolution of pancreatic tumors in human patients Yachida et al; Campbell et al Nature, 497 (2010) Long silent period

Generating clones of lgl mutant cells in normal tissue hsFLP tub-Gal4 UAS-GFP o o l ll o FRT o l tub-Gal80 I II tub-Gal4 UAS-GFP o o l ll o FRT o I II hsFLP lgl M l l + l l Heat shock G2 Mitosis G1 Mimicking how tumours normally appear: clones of oncogenic cells growing in normal tissue

Mutant lgl or rab5 clones are eliminated by cell competition lgl - Menéndez et al PNAS 2010 lgl mutant clones 48hrs after initiation rab5 mutant clones 72 and 96 hrs after initiation lgl - Casp3 lglpuc Casp3 Casp Saavedra et al unpublished The elimination of the tumorous cells is mediated by JNK activity and acts at short distance Additional evidence: Igaki et al 2009; Chen et al 2012 rab5-siRNA Casp

Apoptosis in the borders of overgrowing lgl - ras V12 clones lgl ras V12 Casp3 lgl ras V12 Casp3 Doomed clone Isolated patch of tumour cells being eliminated Mass of overgrowing tumour tissue showing apoptosis at the borders

Microenvironment Model of Tumour Formation in imaginal discs No tumour Invasive tumour The formation of a microenvironment through clone merging allows to escape cell competition Cell competition starts Vv vVv v Vv vVv v

Small group of unprotected cells: aborted tumour Group of protected cells: developing tumour Dying peripheral cells scrib - ras V12 Casp3 Non-tumour cells Fast proliferating inner cells Visualización del modelo de micro-ambiente protector

How much of this is relevant to human tumours? Stratton et al Nature 458, (2009) “…with at least 350 (1.6%) of the approx protein-coding genes in the human genome reported to show recurrent somatic mutations in cancer with strong evidence that these contribute to cancer development.” “The size of the full repertoire of human cancer genes is a matter of speculation. However, studies in mice have suggested that more than 2000 genes, when appropriately altered, may have the potential to contribute to cancer development” From our data we might speculate that mammalian tumours might not be clonal events Mammalian apoptotic cells are also known to secrete growth factors (Prostaglandine E2, PGE2), suggesting apoptosis may promote tumour growth (Li et al Sci. Signal 2010; Huang et al Nature Medicine 2011)

A Nusslein-Volhard y Wieschaus se les concedió en 1995 el Premio Nobel en Fisiología y Medicina por esta publicación Drosophila y el Cancer hedgehog

El gen Hedgehog y el Cancer: muchos tumores de mamíferos están causados por un exceso de actividad de la función hedgehog Forma activaForma inactiva Forma activa

Se han encontrado substancias que inhiben la función tumorigénica de hedgehog Inhibición por ciclopamina de tumores en ratón Nature, 2001; 2003

Rubin and de Sauvage Nature Reviews Drug Discovery 5, 1026–1033 (2006) Búsqueda de fármacos con propiedades similares a la ciclopamina Publicación en Science con los primeros datos en pacientes humanos