Strong evidence supports the concept that mammalian target of rapamycin (mTOR) regulates essential cell processes and dysregulation of mTOR signaling leads to pathogenesis of several debilitating human conditions. Aberrant activation of mTORC1 signaling contributes to malignant behavior of cancer cells by controlling proliferation, invasion, and metastasis. By studying the enhancer of akt1-7 (EAK-7) in self-renewal of human embryonic stem cells, we identified a novel effector of the mTORC1 pathway and provisionally named the human ortholog, mammalian EAK-7 (mEAK-7), due to its original identification in Caenorhabditis elegans. In nematodes, EAK-7 negatively affects longevity through regulation of FoxO transcription factors. Yet, while there is no functional characterization of mEAK-7 (also known as expressed sequence tag KIAA109 or TDLC1), there are examples in the literature that demonstrate upregulated mEAK-7 gene expression and copy number amplification in cancer. We discovered that some cancer cell lines derived from head and neck squamous cell carcinomas (HNSCC), non-small lung carcinomas (NSCLC), and breast carcinomas express detectable protein levels of mEAK-7, while somatic cells we screened do not. Moreover, more than half of the HNSCC cell lines screened in our lab resulted in mEAK-7 positive (mEAK-7+) cancers. This suggested to us that mEAK-7 may play a role in tumorigenesis. Coupled with the fact that mTORC1 signaling is amplified in HNSCC suggests that mEAK-7 may, in part, be responsible for the pathogenesis of HNSCC. With increasing interest in developing mTOR kinase inhibitors to treat HNSCC patients, we will determine the mechanisms by which mEAK-7 functions to support the progression of HNSCC. As an aspiring dentist-scientist, I am primarily interested in HNSCC tumorigenesis in relation to mEAK-7 function under severe DNA damage (X-irradiation) To this end, our central hypothesis is that mEAK-7 functions as a positive regulator of mTORC1 signaling under DNA damage in HNSCC. Canonical mTORC1 signaling utilizes nutrient rich conditions (insulin, amino acids, high energy levels) for activation of this evolutionarily conserved pathway. We discovered a non-canonical pathway that activates mTORC1 signaling after ionizing radiation and provided evidence that mEAK-7 is required for mTORC1 activation under DNA damage in HNSCC. Treatment options for HNSCC patients include 1) surgery and/or 2) chemo- or radio-therapy. However, HNSCC patients that experience chemo- or radio- resistance typically have poor clinical prognoses and there is a lack of well-defined biological markers indicative of this malignant process. Thus, our overarching goal of this F30 application will be to elucidate the role of mEAK-7 in HNSCC, determine the extent to which mEAK-7 plays a role in tumorigenesis, and if mEAK-7 is a HNSCC biomarker.

Public Health Relevance

Head and neck squamous cell carcinoma (HNSCC) patients exhibit genomic deletions and mutations that allow for amplified mTORC1 signaling. While there has been great progress in understanding the pathogenesis of HNSCC, the underlying biomarkers that signify this disease is largely unknown. The standard treatment for HNSCC patients is chemotherapeutics or radiation therapy. Unfortunately, HNSCC patients succumb to their disease due to their tumors gaining chemo- or radio- resistance and this is linked to amplified mTORC1 signaling. To that end, we have identified a novel effector of the mTORC1 signaling pathway that is prominent in HNSCC. Mammalian EAK-7 (mEAK-7) activates mTORC1 signaling through a non-canonical pathway in response to DNA damage (chemotherapeutics, ionizing radiation, and DNA stress). The objective of this application is to 1) elucidate the mechanism of action by which mEAK-7 exerts on mTORC1 signaling in HNSCC and 2) determine if mEAK-7 plays an important functional role in HNSCC tumorigenesis. Findings from these studies would strongly support the rationale to develop specific small-molecule inhibitors of mEAK-7 for the treatment of HNSCC patients.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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NIDR Special Grants Review Committee (DSR)
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Frieden, Leslie A
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University of Michigan Ann Arbor
Schools of Dentistry/Oral Hygn
Ann Arbor
United States
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Topal, Tu?ba; Hong, Xiaowei; Xue, Xufeng et al. (2018) Acoustic Tweezing Cytometry Induces Rapid Initiation of Human Embryonic Stem Cell Differentiation. Sci Rep 8:12977