Activin and TGFβ use diverging mitogenic signaling in advanced colon cancer.

Jessica Bauer,Daniel R Principe,Jonas J Staudacher,Barbara Jung,Paul J Grippo,Timothy Carroll,Lars Eckmann,Martina E Spehlmann,Ozkan Ozden,Naomi Akagi

doi:10.1186/s12943-015-0456-4

Abstract

BackgroundUnderstanding cell signaling pathways that contribute to metastatic colon cancer is critical to risk stratification in the era of personalized therapeutics. Here, we dissect the unique involvement of mitogenic pathways in a TGFβ or activin-induced metastatic phenotype of colon cancer.MethodMitogenic signaling/growth factor receptor status and p21 localization were correlated in primary colon cancers and intestinal tumors from either AOM/DSS treated ACVR2A (activin receptor 2) −/− or wild type mice. Colon cancer cell lines (+/− SMAD4) were interrogated for ligand-induced PI3K and MEK/ERK pathway activation and downstream protein/phospho-isoform expression/association after knockdown and pharmacologic inhibition of pathway members. EMT was assessed using epithelial/mesenchymal markers and migration assays.ResultsIn primary colon cancers, loss of nuclear p21 correlated with upstream activation of activin/PI3K while nuclear p21 expression was associated with TGFβ/MEK/ERK pathway activation. Activin, but not TGFβ, led to PI3K activation via interaction of ACVR1B and p85 independent of SMAD4, resulting in p21 downregulation. In contrast, TGFβ increased p21 via MEK/ERK pathway through a SMAD4-dependent mechanism. While activin induced EMT via PI3K, TGFβ induced EMT via MEK/ERK activation. In vivo, loss of ACVR2A resulted in loss of pAkt, consistent with activin-dependent PI3K signaling.ConclusionAlthough activin and TGFβ share growth suppressive SMAD signaling in colon cancer, they diverge in their SMAD4-independent pro-migratory signaling utilizing distinct mitogenic signaling pathways that affect EMT. p21 localization in colon cancer may determine a dominant activin versus TGFβ ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGFβ family receptors.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0456-4) contains supplementary material, which is available to authorized users.

Highlights

Colon cancer remains the second deadliest cancer in the United States with an estimated 136,830 new cases and 50,310 deaths in 2014 [1]
In primary colon cancers, loss of nuclear p21 correlated with upstream activation of activin/PI3K while nuclear p21 expression was associated with TGFβ/MEK/ERK pathway activation
Conclusion: activin and TGFβ share growth suppressive SMAD signaling in colon cancer, they diverge in their SMAD4-independent pro-migratory signaling utilizing distinct mitogenic signaling pathways that affect epithelial to mesenchymal transition (EMT). p21 localization in colon cancer may determine a dominant activin versus TGFβ ligand signaling phenotype warranting further validation as a therapeutic biomarker prior to targeting TGFβ family receptors

Summary

Introduction

Colon cancer remains the second deadliest cancer in the United States with an estimated 136,830 new cases and 50,310 deaths in 2014 [1]. Understanding the switch to metastatic behavior and Recent efforts in cancer genome comprehensive sequencing have confirmed key genes whose mutations can drive tumorigenesis [2] and have solidified components of the Transforming Growth Factor (TGF) β superfamily as drivers of pathogenesis in colon cancer. These include inactivating mutations in the TGFβII receptor (TGFBR2), the activin receptor 2A (ACVR2A) and downstream signaling molecule SMAD4 [2]. We dissect the unique involvement of mitogenic pathways in a TGFβ or activin-induced metastatic phenotype of colon cancer

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Results

Discussion

Conclusion