Using a Drosophila tumor model in a genetic screen, we previously completed a genome-wide screen for mutations that cooperate with oncogenic Ras in promoting tumor growth and metastasis. Characterization of several identified mutations revealed unexpected biology and pathways, and especially highlighted the importance of cell-cell interaction and signaling in mediating tumor development and progression. Disruption of cell junction or apical-basal polarity leads to JNK activation, which is essential for tumor cell survivl, basement membrane degradation, tumor cell migration, and the unexpected behavior of interclonal cooperation with oncogenic Ras in promoting tumor growth and metastasis. Indeed, the behavior of tumor cells has long been recognized to be highly influenced by its microenvironment, interaction with surrounding wild type cells, and the extracellular milieu such as components of the extracellular matrix. The focus of our research, thus, logically switches from identifying the involved genes in the current funding period to uncover the molecular, cellular, and developmental mechanisms underlying tumor and host cell interactions for tumor growth and metastasis. We propose the following specific aims: (1) Characterizing novel RasV12 cooperating mutations and mechanisms related to JNK activation. We will characterize several new mutations/genes identified in our screen with the aim to identify and study novel tumor suppressors and to understand how JNK is activated. Our efforts will be focused on characterizing novel RasV12 cooperating mutations/genes that have mammalian orthologs mutated in human cancers and those genes that could help us to understand the causal link between disruption of cell polarity and JNK signaling in tumor development;(2) Dissecting cell-cell interaction and signaling mechanisms in promoting tumor growth and metastasis. We will further dissect the signaling between tumor and surrounding wild type cells that promotes tumor development, and will also characterize a novel tumor suppressor, which defines a new mode of cell-cell interaction via unique multicellular epithelial contacts;and (3) Studying organ-specific metastasis. We have discovered that the fly tumors also exhibit organ-specific metastasis behavior, and will try to identify the molecular basis for this targeted migration and invasion. In summary, having identified causative mutations for epithelial tumors, we are now poised to utilize the power of the Drosophila model organism to explore and unravel the molecular mechanisms underlying intercellular signaling that is central to the understanding of cancer biology.

Public Health Relevance

Cell-cell interaction is critical for maintaining proper epithelial architecture and integrity involved in the regulation of cellular proliferation, adhesion, cell shae, and apoptosis, all of which are aberrant in malignant tumors. Having identified causative mutations for epithelial tumors that share common defects in cell polarity and signaling pathways, we now have the opportunity to use fly tumor model to explore and unravel the molecular mechanisms underlying intercellular signaling that is central to understanding human tumor malignancy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA069408-18
Application #
8627556
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Woodhouse, Elizabeth
Project Start
1996-03-05
Project End
2017-03-31
Budget Start
2014-05-28
Budget End
2015-03-31
Support Year
18
Fiscal Year
2014
Total Cost
$293,351
Indirect Cost
$117,164
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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