The drosophila netrin receptor frazzled/DCC functions as an invasive tumor suppressor

Adrienne Vanzomeren-Dohm, Joseph Sarro, Ellen Flannery, Molly Scheel

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: Loss of heterozygosity at 18q, which includes the Deleted in Colorectal Cancer (DCC) gene, has been linked to many human cancers. However, it is unclear if loss of DCC is the specific underlying cause of these cancers. The Drosophila imaginal discs are excellent systems in which to study DCC function, as it is possible to model human tumors through the generation of somatic clones of cells bearing multiple genetic lesions. Here, these attributes of the fly system were utilized to investigate the potential tumor suppressing functions of the Drosophila DCC homologue frazzled (fra) during eye-antennal disc development. Results: Most fra loss of function clones are eliminated during development. However, when mutant clone cells generated in the developing eye were rescued from death, partially differentiated eye cells were found outside of the normal eye field, and in extreme cases distant sites of the body. Characterization of these cells during development indicates that fra mutant cells display characteristics of invasive tumor cells, including increased levels of phospho-ERK, phospho-JNK, and Mmp-1, changes in cadherin expression, remodeling of the actin cytoskeleton, and loss of polarity. Mutation of fra promotes basement membrane degradation and invasion which are repressed by inhibition of Rho1 signaling. Although inhibition of JNK signaling blocks invasive phenotypes in some metastatic cancer models in flies, blocking JNK signaling inhibits fra mutant cell death, thereby enhancing the fra mutant phenotype. Conclusions: The results of this investigation provide the first direct link between point mutations in fra/DCC and metastatic phenotypes in an animal model and suggest that Fra functions as an invasive tumor suppressor during Drosophila development.

Original languageEnglish
Article number41
JournalBMC Developmental Biology
Volume11
DOIs
StatePublished - 2011

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Drosophila
Colorectal Neoplasms
Neoplasms
Clone Cells
Phenotype
Diptera
Imaginal Discs
Loss of Heterozygosity
Neoplasm Genes
Cadherins
netrin receptors
Actin Cytoskeleton
Point Mutation
Basement Membrane
Cell Death
Animal Models
Mutation

ASJC Scopus subject areas

  • Developmental Biology

Cite this

The drosophila netrin receptor frazzled/DCC functions as an invasive tumor suppressor. / Vanzomeren-Dohm, Adrienne; Sarro, Joseph; Flannery, Ellen; Scheel, Molly.

In: BMC Developmental Biology, Vol. 11, 41, 2011.

Research output: Contribution to journalArticle

Vanzomeren-Dohm, Adrienne ; Sarro, Joseph ; Flannery, Ellen ; Scheel, Molly. / The drosophila netrin receptor frazzled/DCC functions as an invasive tumor suppressor. In: BMC Developmental Biology. 2011 ; Vol. 11.
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abstract = "Background: Loss of heterozygosity at 18q, which includes the Deleted in Colorectal Cancer (DCC) gene, has been linked to many human cancers. However, it is unclear if loss of DCC is the specific underlying cause of these cancers. The Drosophila imaginal discs are excellent systems in which to study DCC function, as it is possible to model human tumors through the generation of somatic clones of cells bearing multiple genetic lesions. Here, these attributes of the fly system were utilized to investigate the potential tumor suppressing functions of the Drosophila DCC homologue frazzled (fra) during eye-antennal disc development. Results: Most fra loss of function clones are eliminated during development. However, when mutant clone cells generated in the developing eye were rescued from death, partially differentiated eye cells were found outside of the normal eye field, and in extreme cases distant sites of the body. Characterization of these cells during development indicates that fra mutant cells display characteristics of invasive tumor cells, including increased levels of phospho-ERK, phospho-JNK, and Mmp-1, changes in cadherin expression, remodeling of the actin cytoskeleton, and loss of polarity. Mutation of fra promotes basement membrane degradation and invasion which are repressed by inhibition of Rho1 signaling. Although inhibition of JNK signaling blocks invasive phenotypes in some metastatic cancer models in flies, blocking JNK signaling inhibits fra mutant cell death, thereby enhancing the fra mutant phenotype. Conclusions: The results of this investigation provide the first direct link between point mutations in fra/DCC and metastatic phenotypes in an animal model and suggest that Fra functions as an invasive tumor suppressor during Drosophila development.",
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