Project Description Project Description

Beichu Guo

The role of inflammasome activation in SK1-mediated breast cancer development.

The long-term goal of this application is to gain functional and mechanistic understanding of sphingolipidinduced inflammasome activation in breast cancer progression and metastasis. Breast cancer is the second leading cause of cancer-related deaths of women, and is the most common type of malignant tumor among women. While early diagnosis and new treatment have significantly improved overall survival in women with breast cancer, there are no known effective therapeutic approaches for women with metastatic diseases, which are ultimately incurable and the primary cause of death in breast cancer. Throughout the U.S., about 40,000 women die each year from breast cancer according to the CDC.

Sphingosine-1-phosphate (S1P), a bioactive lipid, has been demonstrated to play important roles in tumor development, including breast cancer, through its ability to promote tumor cell growth, migration, and invasion. S1P is synthesized by sphingosine kinases SK1 and SK2. S1P initiates various signal events through binding to its receptors on cell membrane. Recent studies also suggest that S1P can function as intracellular signaling molecules via interaction with TRAF2, leading to TNF-induced NF-KappaB activation. In human breast cancer, increased expression of SK1 is correlated with poor prognosis and high incidence of diseases recurrence. Furthermore, sphingolipids have been implicated in various inflammatory diseases. While most of studies on the role of SK1 in cancer have focused on its function in proliferation and survival, the contribution of SK1 and S1P to tumor-associated inflammation is poorly characterized.

Our preliminary data have demonstrated that sphingolipid-induced inflammasomes modulated tumor microenvironment and promoted metastasis. An inflammasome is a multimolecular complex, essential for the cleavage of pro-IL-1Beta into its active form. Our preliminary data show that S1P induced inflammasome activation and IL-1Beta production in macrophages. Using orthotropic breast cancer and transgenic mouse models, we found that breast cancer was associated with inflammasome activation. Our data show that SK1 KO mice, as well as mice deficient for inflammasome components, exhibited much slow tumor growth and lung metastasis, compared with wt mice. Notably, tumor tissues from SK1 KO mice exhibited reduced inflammasome activation and IL-1Beta production. Based on our preliminary studies, we hypothesize that SK1 and S1P modulate tumor microenvironments and promote breast cancer progression through inflammasome activation in tumor-associated macrophages. To test our hypothesis, Aim 1 will determine the effects and mechanism of SK1/S1P-mediated inflammasome activation in tumor microenvironments. Aim 2 will determine how inflammasome and IL-1Beta modulate SK1/S1P function, and whether the SK1/S1P pathway and inflammasome form a positive feedback loop to promote inflammation and tumor progression. We believe that our investigation of the novel pathways connecting sphingolipids and inflammasome activation will advance understanding of the mechanisms responsible for tumor progression and may identify potential therapeutic targets for cancer treatment.

Collaborations/core utilization:

• We will collaborate with Dr. Johnson in this proposal.

• We will also see new collaborations with other investigators from MUSC in the sphingolipid field.

• We will use the Lipidomics core facility to analyze the profile of sphingolipids modulated by

inflammasome activation. We will also use other core facilities including Flow Cytometry Core, Cell and Molecular Imaging Shared Resource, Tissue Biorepository Shared Resource, Proteomics Center and the Biomolecular Mass Spectrometry Facility, and Biostatistics Shared Resource.

Specific plans for grant development with target submission dates:

• Generate sufficient preliminary data of inflammasome and SK1/S1P pathways for grant application.

• Establish new collaborations.

• Publish or submit manuscripts related to SK1 and breast cancer.

• Aim to send a RO1 on 10/5/2014 or 2/5/2015.

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