Dissecting TMEM9, a Wnt Signaling Regulator of Colorectal Cancer
Abstract
Scientific Objective and Rationale: Background: Genetic mutation in genes involved in Wnt signaling (a cellular signaling pathway) leads to colorectal cancer (CRC). Thus, elucidating the regulatory mechanisms of Wnt signaling to allow for its targeted manipulation is imperative to develop better CRC treatment. Goal: Our long-term goal is (i) to unravel distinct molecular mechanisms that promote intestinal tumorigenesis and (ii) to develop therapeutic methods to counter CRC cell proliferation. Knowledge Gap: It is imperative to develop methods blocking Wnt signaling specifically in CRC cells. Preliminary Studies: Our comprehensive approaches identified that transmembrane protein 9 (TMEM9) as a key molecule hyperactivating Wnt signaling. Importantly, TMEM9 is highly expressed in CRC cell, but not in normal cells. Our genetically engineered mouse models also showed that mimicking TMEM9 s high expression initiates development of CRC, which reveals unexpected regulatory mechanism of Wnt signaling via TMEM9 in CRC. Hypothesis: Based on our preliminary results, we hypothesized that targeting TMEM9 inhibits intestinal tumorigenesis. Specific Aims and Study Design: Aim 1: To determine in vivo tumorigenic role of TMEM9. Using genetically engineered mouse models, we will address (1) whether TMEM9 accelerates intestinal tumorigenesis and (2) whether genetic ablation of TMEM9 inhibits CRC development. Aim 2: To Repurpose Clinical Cancer Drugs into Targeting TMEM9 in CRC. We will test clinical cancer drugs specifically targeting TMEM9-Wnt signaling in CRC by drug repurposing. Principal Investigator s (PI s) Career Goal: The PI s career goal is to establish CRC research program with a specific focus on understating Wnt signaling regulatory mechanisms and developing CRC-specific targeted therapies. Ultimate Applicability of the Research: Scientific Impact: The proposed project will have a potential impact on the academic community working on CRC in general, and Wnt signaling in particular. Completion of our study will significantly increase our understanding of how Wnt signaling is aberrantly activated by transmembrane protein and proton pump in CRC. Patient Impact: Better understanding of Wnt signaling will ultimately lead to improvement in CRC treatment option. Due to pivotal roles of Wnt signaling in tissue stem cell regulation, conventional approaches targeting Wnt signaling directly displayed detrimental effects on tissue homeostasis and regeneration. Our approaches manipulating CRC-specific molecule (TMEM9) to block Wnt signaling will allow the design of more efficient and specific therapies. This will result in better treatments with fewer side effects, leading to a significant increase in quality of life. Importantly, our clinical cancer drug repurposing approaches can be immediately translated into CRC treatment. Our study holds strong potential to lead to a reduction in CRC mortality within the next decade. Together, the outcome of our proposed study can be immediately translated into CRC therapeutic treatment by clinical cancer drug repositioning. How to Benefit Active Duty Service Members, Families and Others: During the Vietnam War, Agent Orange (2,4-D and 2,4,5-T) and other herbicides were sprayed by the U.S. military. In addition, many Veterans were also exposed to ionizing radiation during testing nuclear weapons and serving in Japan. The exposure to ionizing radiation or Agent Orange during military service was shown to be associated with various human cancers including CRC. Therefore, there is urgent need to develop therapeutic approaches specifically targeting CRC, which is highly relevant to military beneficiaries.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510140
Entities
People
- Jae-il Park
Organizations
- United States Army
- University of Texas at Austin