IQGAP1 is an oncogenic target in canine melanoma.

Ashley M. Zehnder,Poornima H. Neela,Becky H. Lee,Michael S. Kent

doi:10.1371/journal.pone.0176370

Ashley M. Zehnder, Poornima H. Neela + Show 2 more

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https://doi.org/10.1371/journal.pone.0176370

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Journal: PloS one	Publication Date: Apr 26, 2017
Citations: 10	License type: CC BY 4.0

Affiliation: Stanford University, University of California, Davis

Abstract

Canine oral mucosal melanoma is an aggressive malignant neoplasm and is characterized by local infiltration and a high metastatic potential. The disease progression is similar to that of human oral melanomas. Whereas human cutaneous melanoma is primarily driven by activating mutations in Braf (60%) or Nras (20%), human mucosal melanoma harbors these mutations much less frequently. This makes therapeutic targeting and research modeling of the oral form potentially different from that of the cutaneous form in humans. Similarly, research has found only rare Nras mutations and no activating Braf mutations in canine oral melanomas, but they are still reliant on MAPK signaling. IQGAP1 is a signaling scaffold that regulates oncogenic ERK1/2 MAPK signaling in human Ras- and Raf- driven cancers, including melanomas. To investigate whether IQGAP1 is a potential target in canine melanoma, we examined the expression and localization of IQGAP1 in primary canine melanomas and canine oral melanoma cell lines obtained from the University of California-Davis. Using CRISPR/Cas9 knockout of IQGAP1, we examined effects on downstream ERK1/2 pathway activity and assayed proliferation of cell lines when treated with a peptide that blocks the interaction between IQGAP1 and ERK1/2. We observed that canine IQGAP1 is expressed and localizes to a similar extent in both human and canine melanoma by qPCR, Western blot, and immunofluorescence. Deletion of IQGAP1 reduces MAPK pathway activation in cell lines, similar to effects seen in human BrafV600E cell lines. Additionally, we demonstrated reduced proliferation when these cells are treated with a blocking peptide in vitro.

Highlights

Using naturally occurring models of animal disease to study complex diseases, such as cancer, allows researchers to better translate their findings, as genetically engineered mouse models have severe limitations when attempting to translate therapy to human patients[1]
Examination of the canine IQGAP1 locus reveals many similarities to human IQGAP1, within the portion that has been targeted as a cancer therapeutic, the WW region (Fig 1B–lower panel)
This contrasts with the degree of dissimilarity between human and mouse IQGAP1 evident in the upper UCSC track and in the WW domain highlighted in red (Fig 1B– upper and lower panel)

Summary

Introduction

Using naturally occurring models of animal disease to study complex diseases, such as cancer, allows researchers to better translate their findings, as genetically engineered mouse models have severe limitations when attempting to translate therapy to human patients[1]. Canine mucosal melanoma offers a unique model to study responses to signaling and therapeutics[2]. It is similar to human mucosal melanomas in that activating Braf and Nras mutations are very. Canine oral melanomas are dependent on AKT and MAPK signaling[6, 7] and have altered expression of tyrosinase, p16, Pten and P53 similar to what is observed in human melanomas[8, 9]. The clinical progression of canine oral melanomas is similar to that of human oral mucosal melanomas as both are locally invasive and often metastasize through the lymphatic system. The prognosis of oral melanomas in humans and dogs is poor because it often recurs even with multimodal therapy including surgery, radiation, and chemotherapy[10]

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