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Using Drosophila melanogaster to map human cancer pathways

Nature Reviews Cancer volume 5, pages 626–639 (2005)Cite this article

Key Points

  • The conservation of signalling pathways in Drosophila melanogaster enables modelling of most of the hallmarks of mammalian cancer, except telomere maintenance and angiogenesis.

  • Misregulation of most genes/pathways result in only 1–2 of the hallmarks of cancer, and in many cases overgrowth is restrained due to compensatory mechanisms.

  • Misregulation of genes/signalling pathways in clones of cells within a wild-type background can trigger non-cell-autonomous compensatory effects on the surrounding normal tissue, thereby maintaining tissue-size homeostasis.

  • Models of cell migration in D. melanogaster have uncovered novel potential invasion/metastasis genes.

  • Homozygous mutants of the neoplastic tumour suppressors scribble (scrib), discs large 1 (dlg1) and lethal (2) giant larvae (l(2)gl) exhibit most of the hallmarks of cancer, including the ability to invade/metastasize.

  • A new generation of screens attempt to model the development of mammalian tumours by analysing the cooperation of tumour suppressors and oncogenes in clones within an otherwise normal fly. These screens revealed that while scrib-mutant clones alone do not overgrow, strong cooperation is observed between scrib mutants and oncogenic Ras or Notch, resulting in invasive neoplastic tumours. Mutations in other cell-polarity genes also have a crucial role in restraining the pro-tumorigenic effects of oncogenic Ras.

Abstract

The development of human cancer is a multistep process, involving the cooperation of mutations in signalling, cell-cycle and cell-death pathways, as well as interactions between the tumour and the tumour microenvironment. To dissect the steps of tumorigenesis, simple animal models are needed. This article discusses the use of the genetically amenable, multicellular organism, the vinegar fly Drosophila melanogaster. In particular, recent studies have highlighted the power of D. melanogaster for examining cooperative interactions between tumour suppressors and oncogenes and for generating in vivo models of tumour development and metastasis.

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Figure 1: The hallmarks of cancer in Drosophila melanogaster imaginal discs.
Figure 2: Regulation of epithelial polarity.
Figure 3: Pathways mediating cooperation between scribble mutants and RasACT or NotchACT.
Figure 4: Pathways mediating cooperation with RasACT to form metastatic tumours.

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Acknowledgements

We thank P. Humbert and L. Quinn for comments on this review and Laura Johnston for helpful discussions. A.M.B. is supported by a National Institutes of Health grant and a National Health and Medical Research Council (NHMRC) grant, and H.E.R. by an NHMRC Senior Fellowship. We apologise for all studies we could not cite due to space limitations.

Author information

Authors and Affiliations

  1. Research Division, Cell Cycle and Development Group, Peter MacCallum Cancer Centre, 7 St Andrew's Place, East Melbourne, 3002, Victoria, Australia

    Anthony M. Brumby & Helena E. Richardson

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  1. Anthony M. Brumby
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Correspondence to Anthony M. Brumby or Helena E. Richardson.

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Supplementary information

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DATABASES

Flybase

aPKC

Archipelago

bam

baz

brat

Buffy

Cdc42

Dacapo

Diap1

dlg1

DPP

hyd

jaguar

l(2)gl

l(2)tid

l(3)mbt

MER

Moe

Myoblast city

Notch

otu

Patched

PATJ

PNT

Pvr

Rac1

scrib

sdt

SEMA-5C

sho

slik

Taiman

TRE1

warts

WG

FURTHER INFORMATION

Berkeley Drosophila Genome Project

Fly Genes in Cancer Research

Homophila

FlyGRID

Glossary

EXTRACELLULAR MATRIX

An organized array of extracellular proteins, such as laminin and fibronectin, that acts as anchors and receptors for the basally localized transmembrane proteins, the integrins.

ECTOPIC DIFFERENTIATION

Cells that differentiate in environments where differentiation would not normally occur under physiological conditions.

IMAGINAL DISC

A single-cell layer epithelial tissue in the larvae that gives rise to adult structures such as the eyes, wings and legs.

ECTOPIC PROLIFERATION

Proliferation of cells in environments that do not normally support their proliferation, or in tissue compartments where cells are normally fully differentiated and non-proliferative.

UBIQUITIN LIGASE

A protein complex that transfers ubiquitin (a 76 residue protein) from an E2 ubiquitin-conjugating enzyme to the substrate, thereby tagging it for ubiquitin-mediated degradation.

ANOIKIS

Cell death that ensues following loss of contact between the cell and the extracellular matrix

EPITHELIAL–MESENCHYMAL TRANSITION

The transition from a highly polarized epithelial cell to a migratory mesenchymal cell that occurs in development and in cancer progression.

CELL POLARITY

The structure, or shape, of a cell that is determined by the specific location of membrane-localized protein complexes along the apical–basal axis.

CONTACT INHIBITION

The arrest of the cell cycle in G1 phase, which occurs when cell density increases to confluence in culture, mediated by cell–cell contact through cadherins at the adherens junction.

ADHERENS JUNCTIONS

Cell–cell junctions composed of cadherins and catenins. Cadherins are transmembrane proteins that form contacts with each other extracellularly, and intracellularly anchor to the actin cytoskeleton through catenins.

ZONULA ADHERENS

Forms from coalescence of the adherens junctions, and creates a barrier that separates the cell into apical and basolateral membrane domains.

SEPTATE JUNCTIONS

Drosophila melanogaster cell–cell junctions, where Scribbled and Discs large 1 are located, located basal to the adherens junctions.

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Brumby, A., Richardson, H. Using Drosophila melanogaster to map human cancer pathways. Nat Rev Cancer 5, 626–639 (2005). https://doi.org/10.1038/nrc1671

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