Drosophila Approaches to Cancer Laboratory
The spread of malignant cells from the primary tumour to distant sites, or metastasis, is the major cause of death in cancer patients. The biology of metastasis is, however, still poorly understood. Recent investigations suggest a paradigm shift: cellular invasion and migration could occur early during tumourigenesis and with a predominant role of the normal, untransformed tissue surrounding the tumour, the ‘tumour microenvironment’.
The contributions of the microenvironment are best studied in vivo. The fruit fly Drosophila melanogaster offers a unique research opportunity due to its amenable genetics, short life cycle and conserved signalling pathways with low genetic redundancy. Remarkably, and despite the apparent caveat of a long evolutionary distance from humans, many aspects of cancer biology have been successfully modelled in Drosophila.
Current efforts in the laboratory are aimed at understanding the role of two important aspects of the tumour microenvironment: tumour-related inflammation and the stem cell niche. In terms of the inflammatory response, it is now widely accepted that inflammation can either suppress or promote the development of cancer. The underlying mechanisms that define the output of the immune system are largely unknown. We are investigating how tumour necrosis factor (a key pro-inflammatory cytokine) and epithelial integrity dictate the fate of a pre-malignant lesion.
On the other hand, the hypothesis of the 'cancer stem cell' has recently accumulated definitive evidence. A key question is then to understand the normal and cancerous stem cell niche and the microenvironmental factors capable of either restricting or fuelling stem cell growth. We are investigating this topic in the adult Drosophila intestinal stem cell niche, which has remarkable resemblance to its mammalian counterpart.
Scopelliti A, Bauer C, Cordero JB, Vidal M. Bursicon-alpha subunit modulates dLGR2 activity in the adult Drosophila melanogaster midgut independently to Bursicon-beta. Cell Cycle 15: 1538-44, 2016
Faller WJ, Jackson TJ, Knight JR, Ridgway RA, Jamieson T, Karim SA, Jones C, Radulescu S, Huels DJ, Myant KB, Dudek KM, Casey HA, Scopelliti A, Cordero JB, Vidal M, Pende M, Ryazanov AG, Sonenberg N, Meyuhas O, Hall MN, Bushell M, Willis AE, Sansom OJ. mTORC1-mediated translational elongation limits intestinal tumour initiation and growth. Nature 517: 497-500, 2015
Cordero JB, Ridgway RA, Valeri N, Nixon C, Frame MC, Muller WJ, Vidal M, Sansom OJ. c-Src drives intestinal regeneration and transformation. EMBO J 33: 1474-91, 2014
Lourenço FC, Munro J, Brown J, Cordero J, Stefanatos R, Strathdee K, Orange C, Feller SM, Sansom OJ, Vidal M, Murray GI, Olson MF. Reduced LIMK2 expression in colorectal cancer reflects its role in limiting stem cell proliferation. Gut 63: 480-93, 2014
Macagno JP, Diaz Vera J, Yu Y, MacPherson I, Sandilands E, Palmer R, Norman JC, Frame M, Vidal M. FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells. PLoS Genet 10: e1004262, 2014
Parisi F, Stefanatos RK, Strathdee K, Yu Y, Vidal M. Transformed epithelia trigger non-tissue-autonomous tumor suppressor response by adipocytes via activation of Toll and Eiger/TNF signaling. Cell Rep 6: 855-67, 2014
Scopelliti A, Cordero JB, Diao F, Strathdee K, White BH, Sansom OJ, Vidal M. Local control of intestinal stem cell homeostasis by enteroendocrine cells in the adult Drosophila midgut. Curr Biol 24: 1199-211, 2014
Myant KB, Cammareri P, McGhee EJ, Ridgway RA, Huels DJ, Cordero JB, Schwitalla S, Kalna G, Ogg EL, Athineos D, Timpson P, Vidal M, Murray GI, Greten FR, Anderson KI, Sansom OJ. ROS production and NF-kappaB activation triggered by RAC1 facilitate WNT-driven intestinal stem cell proliferation and colorectal cancer initiation. Cell Stem Cell 12: 761-73, 2013
Myant KB, Scopelliti A, Haque S, Vidal M, Sansom OJ, Cordero JB. Rac1 drives intestinal stem cell proliferation and regeneration. Cell Cycle 12: 2973-7, 2013
Cordero JB, Stefanatos RK, Scopelliti A, Vidal M*, Sansom OJ*. Inducible progenitor-derived Wingless regulates adult midgut regeneration in Drosophila. EMBO J 31(19): 3901-17, 2012 *corresponding authors
Cordero JB, Stefanatos RK, Myant, K, Vidal M, Sansom OJ. Non-autonomous Jak/Stat and EGFR signaling crosstalk mediate intestinal stem cell proliferation following Apc loss in the Drosophila adult midgut. Development 139(24): 4524-35, 2012
Heller E, Hurchla MA, Xiang J, Chen S, Schneider J, Joeng K, Vidal M, Goldberg L, Deng H, Hornick MC, Prior JL, Piwnica-Worms D, Long F, Cagan R, Weilbaecher KN. Hedgehog signaling inhibition blocks growth of resistant tumors through effects on tumor microenvironment. Cancer Res 72(4): 897-907, 2012