Colorectal cancer (CRC) remains deadly due to metastatic disease and there is a fundamental gap in understanding how CRC metastases form. Transforming growth factor-beta (TGF?) promotes metastatic CRC at later stages and TGF? inhibitors are in early phase clinical trials, but their suboptimal performance may be due to the lack of appreciation for its family member activin, which itself has distinct prometastatic actions. Our preliminary studies indicate that activin and TGF? function should be interpreted as a complexly intertwined network and further, that tumor stroma potentiates prometastatic activin/TGF? signaling. As activin has been understudied in this context, the overall goal of this application is to elucidate combined prometastatic mechanisms of activin and TGF? signaling in CRC with a future goal of allowing metastatic risk assessment and future niche-specific effective activin/TGF? inhibitor-based treatments. The central hypothesis is that activin/TGF? trigger distinct signaling pathways that potentiate each other to promote metastatic CRC via stromal amplification with the rationale that understanding the underlying mechanisms in individual CRC tumors will allow risk stratification and more effective targeted treatment which minimize adverse events. This hypothesis will be investigated with these three aims: 1) to elucidate the complementary pro-invasive actions and cross-regulation of activin/TGF? in CRC cells and surrounding stroma, 2) to examine the in vivo role of activin/TGF? signaling in CRC metastasis and 3) to fully delineate activin/TGF? pathway status for prediction of CRC metastasis and outcome. For this, we will use colon cancer cell models with a spectrum of activin/TGF? signaling status from wild type to fully abrogated with and without activin/TGF? wild type GI fibroblasts to assess the impact of disrupting TGF?-induced pro-metastatic activin signaling. Our endpoints include examination of ligand production; canonical and non-canonical effector signaling; and growth suppression versus pro-metastatic function. To address the impact of pathway disruption in vivo, both surgical splenic implantation and transgenic APC/KRAS murine models of CRC metastasis will be used to determine effects of loss or augmentation of activin and TGF? signaling or a combination thereof on liver metastasis and outcome. Lastly, clinical implications of activin/TGF? cross-play on metastasis and outcome in human CRC will be examined via three complementary and comprehensive CRC cohorts. These studies are innovative as they depart from the current dogma of single pathway assessment in TGF? and related signaling, employ novel techniques and models allowing integration of tumoral stromal effects and are significant, as they will pave the way to tailored activin/TGF? pathway and niche-specific inhibition based on individual signaling status to target metastatic disease in CRC.

Public Health Relevance

This project is highly relevant to public health, as currently in the U.S., approximately 50,000 people die yearly from CRC with the vast majority due to metastatic disease for which adequate treatment is still lacking. The proposed studies aim to understand the mechanisms and cross-regulation of two signaling pathways that are important in colon cancer metastasis to allow functional assessment in toto and to better select patients for treatments based on individual tumor biology. This is fully in line with the NIH's recent renewed mission in the ?war on cancer? as well as ?Precision Medicine? by combining both aspects.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA141057-09
Application #
10126193
Study Section
Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
Program Officer
Ault, Grace S
Project Start
2010-09-27
Project End
2022-06-30
Budget Start
2020-04-01
Budget End
2020-06-30
Support Year
9
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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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
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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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