Journal article
Constitutive K-Ras(G12D) Activation of ERK2 Specifically Regulates 3D Invasion of Human Pancreatic Cancer Cells via MMP-1
Molecular cancer research, v 10(2)
01 Feb 2012
PMID: 22160930
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Pancreatic ductal adenocarcinomas (PDAC) are highly invasive and metastatic neoplasms commonly unresponsive to current drug therapy. Overwhelmingly, PDAC harbors early constitutive, oncogenic mutations in K-Ras(G12D) that exist prior to invasion. Histologic and genetic analyses of human PDAC biopsies also exhibit increased expression of extracellular signal-regulated kinase (ERK) 1/2 and proinvasive matrix metalloproteinases (MMP), indicators of poor prognosis. However, the distinct molecular mechanisms necessary for K-Ras/ERK1/2 signaling and its influence on MMP-directed stromal invasion in primary human pancreatic ductal epithelial cells (PDEC) have yet to be elucidated in three-dimensions. Expression of oncogenic K-Ras(G12D) alone in genetically defined PDECs reveals increased invadopodia and epithelial-to-mesenchymal transition markers, but only when cultured in a three-dimensional model incorporating a basement membrane analog. Activation of ERK2, but not ERK1, also occurs only in K-Ras(G12D)-mutated PDECs cultured in three-dimensions and is a necessary intracellular signaling event for invasion based upon pharmacologic and short hairpin RNA (shRNA) inhibition. Increased active invasion of K-Ras(G12D) PDECs through the basement membrane model is associated with a specific microarray gene expression signature and induction of MMP endopeptidases. Specifically, MMP-1 RNA, its secreted protein, and its proteolytic cleavage activity are amplified in K-Ras(G12D) PDECs when assayed by real-time quantitative PCR, ELISA, and fluorescence resonance energy transfer (FRET). Importantly, shRNA silencing of MMP-1 mimics ERK2 inhibition and disrupts active, vertical PDEC invasion. ERK2 isoform and MMP-1 targeting are shown to be viable strategies to attenuate invasion of K-Ras(G12D)-mutated human pancreatic cancer cells in a three-dimensional tumor microenvironment. Mol Cancer Res; 10(2); 183-96. (C)2011 AACR.
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Details
- Title
- Constitutive K-Ras(G12D) Activation of ERK2 Specifically Regulates 3D Invasion of Human Pancreatic Cancer Cells via MMP-1
- Creators
- Gregory P. Botta - Drexel UniversityMauricio J. Reginato - Drexel UniversityMaximilian Reichert - Univ Penn, Sch Med, Div Gastroenterol, Philadelphia, PA 19104 USAAnil K. Rustgi - Univ Penn, Sch Med, Div Gastroenterol, Philadelphia, PA 19104 USAPeter I. Lelkes - Drexel University
- Publication Details
- Molecular cancer research, v 10(2)
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 14
- Grant note
- F30 DK088402-01 / NIDDK; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) NTI R01CA155413 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01DK060694 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R01 DK060694 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01 CA155413-01 / NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000300613300001
- Scopus ID
- 2-s2.0-84857223882
- Other Identifier
- 991019169616804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Cell Biology
- Oncology