NDLI: An mDia2/ROCK Signaling Axis Regulates Invasive Egress from Epithelial Ovarian Cancer Spheroids

Content Provider	PubMed Central
Author	Pettee, Krista M. Dvorak, Kaitlyn M. Nestor-kalinoski, Andrea L. Eisenmann, Kathryn M.
Editor	Aspenstrom, Pontus
Copyright Year	2014
Abstract	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.
Related Links	http://dx.doi.org/10.1371/journal.pone.0090371
Starting Page	90371
File Format	PDF
ISSN	19326203
e-ISSN	19326203
Journal	PLoS ONE
Issue Number	2
Volume Number	9
Language	English
Publisher	Public Library of Science
Publisher Date	2014-02-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Agricultural and Biological Sciences(all) Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

BRCA1 Regulates Follistatin Function in Ovarian Cancer and Human Ovarian Surface Epithelial Cells

Novel Epigenetic CREB-miR-630 Signaling Axis Regulates Radiosensitivity in Colorectal Cancer

NuMA Overexpression in Epithelial Ovarian Cancer

Variation in Cell Signaling Protein Expression May Introduce Sampling Bias in Primary Epithelial Ovarian Cancer

Polymorphisms in Stromal Genes and Susceptibility to Serous Epithelial Ovarian Cancer: A Report from the Ovarian Cancer Association Consortium

The MyD88+ Phenotype Is an Adverse Prognostic Factor in Epithelial Ovarian Cancer

ARID3B Directly Regulates Ovarian Cancer Promoting Genes

Association between Common Germline Genetic Variation in 94 Candidate Genes or Regions and Risks of Invasive Epithelial Ovarian Cancer

Correction: The MyD88+ Phenotype Is an Adverse Prognostic Factor in Epithelial Ovarian Cancer

An mDia2/ROCK Signaling Axis Regulates Invasive Egress from Epithelial Ovarian Cancer Spheroids

Similar Documents

BRCA1 Regulates Follistatin Function in Ovarian Cancer and Human Ovarian Surface Epithelial Cells

Novel Epigenetic CREB-miR-630 Signaling Axis Regulates Radiosensitivity in Colorectal Cancer

NuMA Overexpression in Epithelial Ovarian Cancer

Variation in Cell Signaling Protein Expression May Introduce Sampling Bias in Primary Epithelial Ovarian Cancer

Polymorphisms in Stromal Genes and Susceptibility to Serous Epithelial Ovarian Cancer: A Report from the Ovarian Cancer Association Consortium

The MyD88+ Phenotype Is an Adverse Prognostic Factor in Epithelial Ovarian Cancer

ARID3B Directly Regulates Ovarian Cancer Promoting Genes

Association between Common Germline Genetic Variation in 94 Candidate Genes or Regions and Risks of Invasive Epithelial Ovarian Cancer

Correction: The MyD88+ Phenotype Is an Adverse Prognostic Factor in Epithelial Ovarian Cancer

An mDia2/ROCK Signaling Axis Regulates Invasive Egress from Epithelial Ovarian Cancer Spheroids