Metastasis is the major cause of mortality for cancer patients. However, the genetic basis for tumor progression and metastasis is largely unknown. Given that multiple genetic alterations occur during tumor initiation and progression, it has been difficult to find families with inherited mutations for both tumorigenesis and metastasis. The genomes of malignant tumor cells are often destabilized, which makes it a daunting challenge to pinpoint the causative alterations for tumor progression. Furthermore, metastasis involves multiple tissues and it is particularly difficult to study the process in tissue culture cells. Finally, tumor progression in humans and mammals takes a long period of time, which adds additional complication for experimental research. We have developed a Drosophila model for metastasis and have performed a genome-wide screen to identify mutations promoting tumor progression and metastasis. About 100 mutations have been identified which collaborate with oncogenic Ras in promoting tumor progression and metastasis in flies. These fly tumors exhibit a full spectrum of metastatic phenotypes observed in human malignant cancers including loss of cell adhesion, degradation of basement membrane, migration, invasion, and secondary tumor formation. This fly tumor metastasis model and the identified mutations provide a unique opportunity to dissect metastatic behavior in vivo and the mechanism underlying such phenomenon. We propose the following specific aims: (1) Genetic and phenotypic characterization for the recovered metastasis-promoting mutations to identify the genes that disrupted by these alterations and to document the phenotypic consequence caused by these mutations;and (2) Study molecular mechanism underlying oncogenic cooperation that promotes tumor progression and metastasis. We hope that these studies will improve our understanding of the genetic basis for metastatic behavior. Given that many molecules and pathways are conserved from flies to humans, it is further hoped that these experiments will also contribute to our understanding of some aspects of tumor progression and metastasis in humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA069408-14
Application #
7813918
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
1996-03-05
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
14
Fiscal Year
2010
Total Cost
$309,905
Indirect Cost
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Chabu, Chiswili; Li, Da-Ming; Xu, Tian (2017) EGFR/ARF6 regulation of Hh signalling stimulates oncogenic Ras tumour overgrowth. Nat Commun 8:14688
Ma, Xianjue; Lu, Jin-Yu; Dong, Yongli et al. (2017) PP6 Disruption Synergizes with Oncogenic Ras to Promote JNK-Dependent Tumor Growth and Invasion. Cell Rep 19:2657-2664
Willsey, Helen Rankin; Zheng, Xiaoyan; Carlos Pastor-Pareja, José et al. (2016) Localized JNK signaling regulates organ size during development. Elife 5:
Gayle, Sophia; Pan, Yukun; Landrette, Sean et al. (2015) piggyBac insertional mutagenesis screen identifies a role for nuclear RHOA in human ES cell differentiation. Stem Cell Reports 4:926-38
Mishra-Gorur, Ketu; Ça?layan, Ahmet Okay; Schaffer, Ashleigh E et al. (2014) Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors. Neuron 84:1226-39
Du, Xingrong; Dong, Yongli; Shi, Hao et al. (2014) Mst1 and mst2 are essential regulators of trophoblast differentiation and placenta morphogenesis. PLoS One 9:e90701
Chabu, Chiswili; Xu, Tian (2014) Oncogenic Ras stimulates Eiger/TNF exocytosis to promote growth. Development 141:4729-39
Ma, X; Li, W; Yu, H et al. (2014) Bendless modulates JNK-mediated cell death and migration in Drosophila. Cell Death Differ 21:407-15
Pastor-Pareja, José Carlos; Xu, Tian (2013) Dissecting social cell biology and tumors using Drosophila genetics. Annu Rev Genet 47:51-74
Pastor-Pareja, José Carlos; Xu, Tian (2011) Shaping cells and organs in Drosophila by opposing roles of fat body-secreted Collagen IV and perlecan. Dev Cell 21:245-56

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