KRas Induces a Src/PEAK1/ErbB2 Kinase Amplification Loop That Drives Metastatic Growth and Therapy Resistance in Pancreatic Cancer

Kelber, Jonathan A.; Reno, Theresa; Kaushal, Sharmeela; Metildi, Cristina; Wright, Tracy; Stoletov, Konstantin; Weems, Jessica M.; Park, Frederick D.; Mose, Evangeline; Wang, Yingchun; Hoffman, Robert M.; Lowy, Andrew M.; Bouvet, Michael; Klemke, Richard L.

doi:10.1158/0008-5472.can-11-3552

Cited by 96 publications

(144 citation statements)

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“…The central role of Src in pancreatic ductal adenocarcinoma metastasis and progression is well documented (39). PEAK1 is also overexpressed in a variety of cancers, including pancreatic ductal adenocarcinoma, in which it associates with an Src-ErbB2 complex to promote cancer progression and metastasis (18). ErbB2-mediated Src activity increases cancer cell migration and invasion (40), and our previous study showed that PEAK1 mediates the formation of an active Src-ErbB2 complex that drives anchorage-independent growth and carcinogenesis (18).…”

Section: Discussionmentioning

confidence: 99%

“…PEAK1 is also overexpressed in a variety of cancers, including pancreatic ductal adenocarcinoma, in which it associates with an Src-ErbB2 complex to promote cancer progression and metastasis (18). ErbB2-mediated Src activity increases cancer cell migration and invasion (40), and our previous study showed that PEAK1 mediates the formation of an active Src-ErbB2 complex that drives anchorage-independent growth and carcinogenesis (18). PEAK1-Src-ErbB2 function in a feed-forward loop; however, the mechanism through which this kinase complex promotes migration remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…GFP (empty vector (EV)) and GFP-PEAK1 (WT PEAK1) were described previously (14), as were sh_2 and shCntrl (17). sh_3 (18) was purchased from Open Biosystems/The RNA Consortium (Thermo Scientific). HT1080 cells stably expressing shCntrl, sh_2, or sh_3 were generated by lentiviral transduction, and positively expressing cells were isolated with puromycin selection or FACS.…”

Section: Methodsmentioning

confidence: 99%

“…We originally identified PEAK1 in a proteomics analysis of proteins enriched in the pseudopodia of migrating cells (17). PEAK1 promotes cancer metastasis and is expressed at high levels in human pancreatic and colon cancer (17,18). Additionally, PEAK1 associates with the actin cytoskeleton and FAs in migrating cells and promotes the elongation of developing FAs (17).…”

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confidence: 99%

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Dynamic Phosphorylation of Tyrosine 665 in Pseudopodium-enriched Atypical Kinase 1 (PEAK1) Is Essential for the Regulation of Cell Migration and Focal Adhesion Turnover

Bristow¹,

Reno

et al. 2013

Journal of Biological Chemistry

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Background: Phosphoregulation of focal adhesion (FA) proteins regulates FA dynamics underlying cell migration. Results: Dynamic phosphoregulation of PEAK1 at Tyr-665 is essential for control of FA dynamics and cell migration. Conclusion: Src family kinases (SFKs) and PEAK1 function cooperatively to control FA dynamics and cell migration. Significance: PEAK1 is a novel SFK-dependent FA regulator and a promising anti-cancer drug target.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Dynamic Phosphorylation of Tyrosine 665 in Pseudopodium-enriched Atypical Kinase 1 (PEAK1) Is Essential for the Regulation of Cell Migration and Focal Adhesion Turnover

Bristow¹,

Reno

et al. 2013

Journal of Biological Chemistry

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“…27 Although it remains to be tested, arguments for an involvement of Src in the KRas-mROS-PKD1 signaling cascade are recent findings showing cooperation of Src and oncogenic KRas in driving pancreatic neoplasia, 28 metastatic growth and therapy resistance in pancreatic cancer. 29 PKD1 can activate NF-kB downstream of ROS, 24,25 and during development of PDA, KRas-mROS-PKD1-NF-kB signaling upregulates the expression of EGF-R, its ligands TGFa and EGF as well as their sheddase ADAM17. 5 Overexpression of EGFR and its ligands occurs frequently in the early development process of PDA.…”

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confidence: 99%

KRas, ROS and the initiation of pancreatic cancer

Störz

2016

Small GTPases

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Oncogenic mutations of KRAS are the most frequent driver mutations in pancreatic cancer. Expression of an oncogenic allele of KRAS leads to metabolic changes and altered cellular signaling that both can increase the production of intracellular reactive oxygen species (ROS). Increases in ROS have been shown to drive the formation and progression of pancreatic precancerous lesions by upregulating survival and growth factor signaling. A key issue for precancerous and cancer cells is to keep ROS at levels where they are beneficial for tumor development and progression, but below the threshold that leads to induction of senescence or cell death. In KRas-driven neoplasia aberrantly increased ROS levels are therefore balanced by an upregulation of antioxidant genes. KEYWORDSKRas; mitochondria; oxidative stress; pancreatic cancer; PanIN; ROS Epidemiological and animal studies suggest that supplementation of dietary antioxidants decreases cancer risk, which implies that increased ROS may play a role in carcinogenesis. 1 Approximately 95% of all pancreatic ductal adenocarcinoma (PDA) show acquisition of activating KRAS mutations, 2 which, due to oncogene-mediated alterations in the cell's metabolism, goes along with increased cellular oxidative stress levels. [3][4][5][6] In mouse models for development of PDA, KRas-caused formation of ROS already is induced in acinar cells and gradually increased during ADM and PanIN formation and progression 5 (Fig. 1).In pancreatic cancer, oncogenic KRas induces the generation of ROS through multiple mechanisms. Typical metabolic changes initiated by tumor cells are, for example, an increase in aerobic glycolysis (Warburg effect) to support growth under hypoxic conditions 7 or altered mitochondrial metabolic activity. 5,6,[8][9][10] Oncogenic KRas can modulate mitochondrial metabolism and ROS generation by regulating hypoxia-inducible factors (HIFs) HIF-1a and HIF-2a, 8 or through regulation of the transferrin receptor (TfR1), which is highly expressed in pancreatic cancers. 11 In addition, KRas can induce suppression of respiratory chain complex I and III to cause mitochondrial dysfunction. 6,12 Decreased mitochondrial efficiency then results in an increased production of ROS. 5 A possible cause is the ROS-mediated occurrence of 4-hydroxy-2-nonenal (4HNE) and 4HNE-adduct formation with macromolecules, which can lead to inhibition of mitochondrial proteins or damage of mtDNA. 5 KRas-induced increases in intracellular ROS levels can also occur via altered NADPH oxidase activities, 1 i.e. due to activation of Rac1-NOX4 signaling. 13 For example, Rac1 in Kras G12D -expressing PanIN1B/PanIN2 is increasingly active when the tumor protein p53-induced nuclear protein 1 (TP53INP1) is knocked out or decreasingly expressed. 14 Other mechanisms by which increases in intracellular ROS can be achieved include enhanced growth factor signaling, 15,16 KRas G12D -induced induction of autophagy-specific genes 5 and 7 (ATG5, ATG7), 17 repression of SESN3, which controls the regeneration of peroxi...

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Open pipelines for integrated tumor genome profiles reveal differences between pancreatic cancer tumors and cell lines

et al. 2015

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We describe open, reproducible pipelines that create an integrated genomic profile of a cancer and use the profile to find mutations associated with disease and potentially useful drugs. These pipelines analyze high-throughput cancer exome and transcriptome sequence data together with public databases to find relevant mutations and drugs. The three pipelines that we have developed are: (1) an exome analysis pipeline, which uses whole or targeted tumor exome sequence data to produce a list of putative variants (no matched normal data are needed); (2) a transcriptome analysis pipeline that processes whole tumor transcriptome sequence (RNA-seq) data to compute gene expression and find potential gene fusions; and (3) an integrated variant analysis pipeline that uses the tumor variants from the exome pipeline and tumor gene expression from the transcriptome pipeline to identify deleterious and druggable mutations in all genes and in highly expressed genes. These pipelines are integrated into the popular Web platform Galaxy at http://usegalaxy.org/cancer to make them accessible and reproducible, thereby providing an approach for doing standardized, distributed analyses in clinical studies. We have used our pipeline to identify similarities and differences between pancreatic adenocarcinoma cancer cell lines and primary tumors.

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KRas Induces a Src/PEAK1/ErbB2 Kinase Amplification Loop That Drives Metastatic Growth and Therapy Resistance in Pancreatic Cancer

Cited by 96 publications

References 37 publications

Dynamic Phosphorylation of Tyrosine 665 in Pseudopodium-enriched Atypical Kinase 1 (PEAK1) Is Essential for the Regulation of Cell Migration and Focal Adhesion Turnover

Dynamic Phosphorylation of Tyrosine 665 in Pseudopodium-enriched Atypical Kinase 1 (PEAK1) Is Essential for the Regulation of Cell Migration and Focal Adhesion Turnover

KRas, ROS and the initiation of pancreatic cancer

Open pipelines for integrated tumor genome profiles reveal differences between pancreatic cancer tumors and cell lines

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