BioMed Research International

Review Article

Modelling Cooperative Tumorigenesis in Drosophila

Table 1

Cooperating genes in Drosophila tumorigenesis.


Cell-autonomous cooperative tumorigenesis
1st mutation/mechanism	2nd mutation/mechanism	Phenotype/references

Cell polarity gene perturbations

Loss of function in apicobasal polarity regulators Results in cell polarity loss, JNK activation, mild Hippo pathway impairment		Neoplastic overgrowth in whole tissue context and cell polarity loss and apoptosis in clonal context (reviewed in [19])

Scribble (scrib, dlg, lgl) and Par and Crb polarity module gene loss of function Scribble module loss of function phenotypes dependent on aPKC activation	Ras^V12 overexpression Dependent on ROS production, TNF (Egr)-JNK signalling, caspase (Dronc) activity Dependent on impairment of Hippo signalling Dependent on PI3K signalling and glutamate utilization	Invasive neoplastic tumours of the larval eye-antennal epithelium [23, 48, 57, 60, 65–68]

scrib loss of function, aPKC-CA overexpression, crb overexpression	Inhibition of JNK signalling	Neoplastic tumour overgrowth in eye-antennal epithelium [66]

lgl or scrib loss of function Results in JNK activation	Ras^V12 overexpression Requires Hippo pathway impairment	Neoplastic tumours in the larval wing epithelium [49]

scrib loss of function Results in JNK activation	Notch^{intra (Act)} overexpression	Invasive neoplastic tumours in the larval eye-antennal epithelium [23, 66, 69]

scrib loss of function Results in JNK activation	Abrupt (BTB-POZ Zn finger transcription factor) overexpression Results in JNK activation Results in Hippo pathway impairment Results in downregulation of differentiation and Ecdysone response genes	Invasive neoplastic tumours in the eye-antennal and wing epithelial tissues [70]

scrib loss of function	Taiman (Ecdysone coactivator) Results in reduced differentiation	Invasive neoplastic tumours in the eye-antennal and wing epithelial tissues [70]

scrib loss of function Results in JNK activation	Slit-Robo2-Ena loss of function	Overgrown tumours in the eye-antennal epithelial tissues [45]

scrib loss of function Results in JNK activation	Slit-Robo overexpression Requires Ena Results in JNK activation and activation of a positive feedback loop	Excessive extrusion and luminal tumour overgrowth in larval eye-antennal epithelial tissues [45]

lgl loss of function Results in Hippo pathway impairment	Inhibition of JNK signalling	Invasive neoplastic tumours of the larval/pupal eye neural-epithelium [71]

lgl loss of function	Myc overexpression	Invasive neoplastic tumours of the larval wing epithelium [50]

lgl loss of function	Hippo pathway impairment	Neoplastic tumours of the larval wing epithelium [49]

lgl loss of function	Notch^{intra (Act)} overexpression	Neoplastic tumours of the larval wing epithelium [72]

scrib, dlg or lgl depletion	cno mutants Results in activation of Ras-MAPK signalling	Enhanced neoplastic tumours of the antennal epithelium [73]

Par-1 overexpression Results in cell polarity loss and Hippo pathway impairment		Eye-antennal and wing tissue overgrowth [74]

Par-1 overexpression	Notch^{intra (Act)} overexpression	Hyperplastic eye-antennal epithelium [75]

Actin cytoskeletal regulators

Activation of Actin cytoskeletal regulators Rac1, RhoGEF2, Pbl, Rho^V14, Rho1, Rok^CAT, sqh^EE Results in activation of JNK signalling and cell morphology changes	(Raf gain-of-function) overexpression	Invasive neoplastic tumours of the larval eye-antennal epithelium [76, 77]

RhoGEF2 overexpression Results in JNK activation and cell morphology changes	Abrupt (BTB-POZ Zn finger transcription factor) overexpression Results in reduced expression of differentiation gene, Dac	Neoplastic tumours of the larval eye-antennal epithelial tissue [78]

Src64B overexpression Results in JNK activation and cell morphology changes	Blocking JNK Rac1-Dia, Ras-MAPK, Hippo pathway impairment	Eye-antennal epithelial tissue overgrowth [79]

csk loss of function (Src activation) Depends on Actin cytoskeleton regulators, JNK activation, STAT activation, Hippo pathway impairment, Wingless (Wnt) expression/signalling and insulin-PI3K signalling	overexpression Promotes cell proliferation and survival	Invasive neoplastic tumours of the larval eye-antennal epithelium [80–85]

Src42A or Src64B overexpression Results in Egr independent activation of JNK and Jak-Stat signalling	overexpression	Neoplastic tumours of the larval eye-antennal and wing epithelium [86]

Src64B overexpression Results in cell morphology changes	Abrupt overexpression Reduces expression of differentiation gene and Dac and Dll	Neoplastic tumours of the larval eye-antennal epithelial tissue [78]

Troponin I overexpression	Ras^V12 overexpression Notch^{intra (Act)} overexpression lgl mutant Ras^V12 overexpression	Tumour overgrowth or neoplastic tumour overgrowth in wing epithelial tissue [87]

Signalling pathway deregulation

Ras^V12 overexpression Results in tissue overgrowth, which depends upon EGF-EGFR activation and Arf6 mediated Hedgehog signalling		Eye-antennal and wing epithelial tissue overgrowth [88]

	TNF-JNK signalling	Invasive neoplastic tumours in the larval eye-antennal epithelium [76, 89–91]

	Immune signalling and activation of JNK	Invasive neoplastic tumours of the adult hindgut epithelium [92]

	Ben/dUev1a E2 ubiquitin ligase overexpression Results in JNK activation (via binding Traf2)	Invasive neoplastic tumours in the larval eye-antennal epithelium [93–95]

	sds22 (PP1) loss of function Results in cell morphology/polarity loss Results in Myosin II, JNK activation	Invasive neoplastic tumours of the larval eye-antennal epithelium [96]

	PP6 phosphatase (FMT, PpV) knock down Results in Tak1-JNK activation	Invasive neoplastic tumours of the eye-antennal epithelium [97]

	Infection/inflammation Results in Imd-dTab2-dTak1-JNK signalling and MMP1 expression	Hindgut epithelial tumour invasion [92, 98]

	Impaired Hippo pathway signalling Results in upregulation of Ras pathway genes, Upd-Jak-Stat signalling	Eye-antennal and wing tissue overgrowth [65, 99]

	Lysosomal protein loss of function—deep orange, carnation, vps16A	Invasive neoplastic tumours of the larval eye-antennal epithelium [100]

	Autophagy loss of function—e.g., Atg8a, Atg7, Atg9, Atg1, Atg13, Syx17 Requires ROS and JNK upregulation	Invasive neoplastic tumours of the larval eye-antennal epithelium [101]

	Chromosome remodelling complex mutation polyhomeotic Depends on ectopic Notch activation	Invasive neoplastic tumours of the larval eye-antennal epithelium [102]

	Chinmo (BTB-POZ Zn finger transcription factor) overexpression	Overgrown tumours in the eye-antennal epithelial tissues [69]

	Fruitless (BTB-POZ Zn finger transcription factor) overexpression	Overgrown tumours in the eye-antennal epithelial tissues [69]

	PTEN knockdown (Elevated PI3K signalling)	Larval-Pupal tracheal epithelial tissue invasive tumours [103]

	apc (Wingless/Wnt) signalling	Adult midgut epithelial tissue overgrowth [104, 105]

	p53, apc, pten knockdown dSmad4, apc, pten knockdown	Adult hindgut epithelial tissue invasive tumours [106]

	pico (MRL) overexpression chickadee (Profilin) overexpression mal (SRF cofactor gene) overexpression Requires JNK-MMP1 activity	Glial cell overgrowth and invasion [107]

EGFR activation/overexpression Depends on Ras and Hh signalling		Eye-antennal and wing epithelial tissue overgrowth [88]

	fat loss of function (Hippo pathway impairment)	Eye-antennal and wing epithelial tissue overgrowth [108]

	bantam micro-RNA expression Results in downregulation of Socs36E Leads to increased Jak-Stat signalling	Invasive overgrowth of the larval wing epithelium [109]

	miR-10 or miR-375 Micro-RNA expression Results in downregulation of Psq transcription factor	Invasive overgrowth of the larval eye-antennal and wing epithelium [52]

	miR-8 Micro-RNA expression Results in downregulation of Peanut protein expression, cytokinesis blockage, formation of polyploid cells	Invasive overgrowth of the larval wing epithelium [110]

	PI3K pathway activation Requires Tor, Sin1, Rictor, Myc, Cyclin D-Cdk4, Rb-E2F and Cdc25 Requires RIOK1, RIOK2	Glia cell invasive brain tumours and eye neural-epithelium tumours [111–113]

Notch^{intra (Act)}/Delta overexpression Results in tissue overgrowth		Eye-antennal and wing tissue overgrowth (reviewed by [114])

overexpression	Mef2 overexpression	Invasive neoplastic tumours of the larval eye neural-epithelium [115]

overexpression	Chinmo (BTB-POZ Zn finger transcription factor) overexpression	Overgrown tumours in the eye-antennal epithelial tissues [69]

overexpression	Fruitless (BTB-POZ Zn finger transcription factor) overexpression	Overgrown tumours in the eye-antennal epithelial tissues [69]

Delta overexpression	Overexpression of transcription factors Psq/Lola (eyeful model)	Invasive tumours larval/pupal eye neural-epithelium, which are capable of differentiation to express ELAV [116]

Delta overexpression	Overexpression of Akt or PI3K (Dp110)	Invasive tumours larval/pupal eye neural-epithelium, which are capable of differentiation (ELAV expression) [117]

Delta overexpression Results in repression of boi gene expression and reduced Hedgehog signalling	Overexpression of mir-7 micro-RNA Results in downregulation of ihog translation and reduced Hedgehog signalling	Eye-antennal disc overgrowth and invasive cells cable of differentiation [118]

Delta overexpression	Overexpression of Zfh1 (Zeb1 family transcription factor gene)	Invasive tumours larval/pupal eye neural-epithelium, which are capable differentiation to express ELAV [119]

Delta overexpression Delta with Pipsqueak/Lola overexpression (eyeful model)	Knockdown of atonal (transcription factor gene) Results in reduced JNK signalling	Invasive tumours larval/pupal eye neural-epithelium, which are capable differentiation to express ELAV [120]

Delta overexpression Delta with Pipsqueak/Lola overexpression (eyeful model)	Knockdown of cut (transcription factor gene) Results in increased reaper expression and elevated PI3K-Akt signalling	Invasive tumours in larval/pupal eye-antennal epithelium, which are capable differentiation to express ELAV [121]

Hippo pathway impairment (Yki overexpression) Results in increased tissue growth through upregulation of cell growth (Myc), proliferation (CycE) and antiapoptotic genes (Diap1), elevation of Upd-Jak-Stat signalling		Increased tissue growth (reviewed by [122])

	BAP (Brahma) complex knockdown (brm, Snr1, mor, Bap111, osa) Results in upregulation of Wingless (Wnt) and Dpp signalling	Neoplastic tumour overgrowth in larval wing epithelial tissue [123]

	Taiman (Ecdysone Receptor coactivator) overexpression Results in expression of germline stem cell factors	Hyperplastic tumour overgrowth in larval wing epithelial tissue [124]

Guidance receptors

Frazzled (Dcc) loss of function and expression of the Caspase inhibitor P35 Results in an invasive phenotype in eye epithelial cells, but cells can differentiate	Inhibition of JNK signalling Requires Rho1	Invasive, but differentiated, tumours in larval/pupal eye-antennal epithelial tissues [125]

Mitotic checkpoint, chromosome instability, DNA damage repair genes

Nek2 (centrosomal kinase) overexpression	Ret^MEN2B overexpression—elevated Ras, PI3K, Src, JNK signalling Ras^V12 Results in Rac1, Rho1, Wg signalling and elevated expression of Diap1, MMP1 Results in PI3K signalling	Invasive tumours in larval eye-antennal epithelial tissue [126]

bub3 knockdown Results in aneuploidy	p35 overexpression to block effector caspase activity	Neoplastic overgrowth of wing epithelial cells [127]

DNA repair or DNA damage checkpoint mutants Depletion of okra (DmRAD54) or spnA (DmRAD51) (Homologous recombination of DNA double strand-breaks in G2) grp (chk1) and mei-41 (ATR) knockdown (DNA damage checkpoint)	Ionizing irradiation and p35 overexpression Results in JNK activation, which leads to MMP1 and Wg upregulation	Overgrowth and cell delamination/migration in the wing epithelial tissue [128]