Activin is a growth suppressive ligand of the TGF? superfamily. It initiates its canonical signaling via a specific receptor, activin receptor 2 (ACVR2) that subsequently phosphorylates activin receptor 1 (ACVR1) to activate a signaling cascade culminating in nuclear translocation of SMAD proteins and growth suppression. We have data showing that ACVR2 protein is lost by distinct mechanisms in human colon cancer regardless of the type of genomic instability and loss is associated with an increase in tumor size in primary colon cancer specimens. Further, activin induces colon cancer cell migration in an ACVR2- dependent manner via activation of mitogenic PI3Kinase signaling, possibly without utilizing SMADs. Additionally, in contrast to TGF?, activin leads to nuclear p21waf down regulation. The goal of this project is to analyze the effects of loss of SMAD-dependent versus SMAD-independent activin signaling on colon cancer characteristics and patient outcomes as well as to dissect mechanisms of activin's distinct effects on migration and cell growth. We hypothesize that mutated ACVR2 interrupts activin signaling causing increased colon cancer cell growth via loss of SMAD-dependent signaling but a decrease in metastatic phenotype via loss of SMAD-independent signaling. Further, we hypothesize that growth suppressive and pro-migratory properties of activin are distinctly regulated via a ligand-specific p21waf1 nuclear export. We will first assess activin and PI3K signaling status in primary colon cancers and metastasis and correlate with patient outcome, followed by assessment of effects of loss of activin and PI3Kinase signaling on intestinal tumors in vivo. Then, using colon cancer cell models with varying ACVR2/PI3K/SMAD4 backgrounds and activin/PI3kinase signaling manipulations, we will examine the specific mechanism of activation of PI3kinase via activin and effects on colon cancer migration in vitro and in vivo employing mouse metastasis models. This will be followed by experiments analyzing the mechanisms of the differential outcome on p21waf1 and its effects on activin-induced SMAD-dependent growth suppression and apoptosis and SMAD-independent migration. This project assesses the specific role of activin signaling and ACVR2 on colon cancer cell growth and migration using human specimens, cellular, and in vivo models.

Public Health Relevance

Colon cancer is the second deadliest cancer in the U.S., with the deaths due largely to metastatic disease. Understanding the genetic mechanisms of how colon cancer metastases form will help to develop better tools to prevent, diagnose, and treat colon cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA141057-02
Application #
8149924
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Ault, Grace S
Project Start
2010-09-27
Project End
2015-07-31
Budget Start
2011-08-01
Budget End
2012-07-31
Support Year
2
Fiscal Year
2011
Total Cost
$276,251
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Staudacher, Jonas J; Yazici, Cemal; Bul, Vadim et al. (2017) Increased Frequency of KRAS Mutations in African Americans Compared with Caucasians in Sporadic Colorectal Cancer. Clin Transl Gastroenterol 8:e124
Jana, Arundhati; Krett, Nancy L; Guzman, Grace et al. (2017) NFkB is essential for activin-induced colorectal cancer migration via upregulation of PI3K-MDM2 pathway. Oncotarget 8:37377-37393
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Principe, Daniel R; DeCant, Brian; Staudacher, Jonas et al. (2017) Loss of TGF? signaling promotes colon cancer progression and tumor-associated inflammation. Oncotarget 8:3826-3839
Staudacher, Jonas J; Bauer, Jessica; Jana, Arundhati et al. (2017) Activin signaling is an essential component of the TGF-? induced pro-metastatic phenotype in colorectal cancer. Sci Rep 7:5569
Ozden, Ozkan; Bishehsari, Faraz; Bauer, Jessica et al. (2016) Expression of an Oncogenic BARD1 Splice Variant Impairs Homologous Recombination and Predicts Response to PARP-1 Inhibitor Therapy in Colon Cancer. Sci Rep 6:26273
Principe, Daniel R; DeCant, Brian; Mascariñas, Emman et al. (2016) TGF? Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis. Cancer Res 76:2525-39
Bauer, Jessica; Staudacher, Jonas J; Krett, Nancy L et al. (2016) Commentary: Activin and TGF? use diverging mitogenic signaling in advanced colon cancer. J Rare Dis Res Treat 1:43-45

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