An mDia2/ROCK signaling axis regulates invasive egress from epithelial ovarian cancer spheroids.
An mDia2/ROCK signaling axis regulates invasive egress from epithelial ovarian cancer spheroids.
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DOI：
10.1371/journal.pone.0090371
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Eisenmann KM
中科院分区：
文献类型：
--
作者：
Pettee KM;Dvorak KM;Nestor-Kalinoski AL;Eisenmann KM
Multi-cellular spheroids are enriched in ascites of epithelial ovarian cancer (OvCa) patients. They represent an invasive and chemoresistant cellular population fundamental to metastatic dissemination. The molecular mechanisms triggering single cell invasive egress from spheroids remain enigmatic. mDia formins are Rho GTPase effectors that are key regulators of F-actin cytoskeletal dynamics. We hypothesized that mDia2-driven F-actin dynamics promote single cell invasive transitions in clinically relevant three-dimensional (3D) OvCa spheroids. The current study is a dissection of the contribution of the F-actin assembly factor mDia2 formin in invasive transitions and using a clinically relevant ovarian cancer spheroid model. We show that RhoA-directed mDia2 activity is required for tight spheroid organization, and enrichment of mDia2 in the invasive cellular protrusions of collagen-embedded OVCA429 spheroids. Depleting mDia2 in ES-2 spheroids enhanced invasive dissemination of single amoeboid-shaped cells. This contrasts with spheroids treated with control siRNA, where a mesenchymal invasion program predominated. Inhibition of another RhoA effector, ROCK, had no impact on ES-2 spheroid formation but dramatically inhibited spheroid invasion through induction of a highly elongated morphology. Concurrent inhibition of ROCK and mDia2 blocked single cell invasion from ES-2 spheroids more effectively than inhibition of either protein alone, indicating that invasive egress of amoeboid cells from mDia2-depleted spheroids is ROCK-dependent. Our findings indicate that multiple GTPase effectors must be suppressed in order to fully block invasive egress from ovarian cancer spheroids. Furthermore, tightly regulated interplay between ROCK and mDia2 signaling pathways dictates the invasive capacities and the type of invasion program utilized by motile spheroid-derived ovarian cancer cells. As loss of the gene encoding mDia2, DRF3, has been linked to cancer progression and metastasis, our results set the stage for understanding molecular mechanisms involved in mDia2-dependent egress of invasive cells from primary epithelial tumors.
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DOI：
10.1016/j.biocel.2007.07.011
发表时间：
2007-01-01
影响因子：
4
作者：
Guarino, Marcello
通讯作者：
Guarino, Marcello
DOI：
10.1083/jcb.200802081
发表时间：
2008-06-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fackler OT;Grosse R
通讯作者：
Grosse R
DOI：
10.1042/bj20110112
发表时间：
2011-07-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Barbolina MV;Burkhalter RJ;Stack MS
通讯作者：
Stack MS
影响因子：
4.8
作者：
Blumenstein, L;Ahmadian, MR
通讯作者：
Ahmadian, MR
影响因子：
5.8
作者：
Bijman, Marcel N. A.;van Berkel, Maria P. A.;Boven, Epie
通讯作者：
Boven, Epie