Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Though this group of cancers is not among the most prevalent in the United States, the incidence rate of HNSCC has steadily increased over the last decade while the 5-year survival rate has remained static. Though there is a general understanding of the risk factors for HNSCC initiation, such as cigarette smoking and alcohol consumption, there is little knowledge regarding the mechanisms of HNSCC progression, particularly modes of invasion and metastasis. Loss of response to Activin A (Act A) signaling, an arm of the TGF? superfamily, has been recently implicated in cancer progression and metastasis. Characteristic Act A signaling has been found to promote apoptosis and growth arrest, as well as potently inhibit angiogenesis. However, Act A expression is commonly upregulated in tumors, compared to normal tissue. This clinical evidence suggests that the cancer cells may acquire resistance to Act A signaling, such as through alterations of proteins involved in the signaling cascade, therefore rendering the cells insensitive to the growth inhibitory effects of Act A. Loss of tumor cell response to Act A signaling may be a result of a downregulation of one or multiple components of the Act A signaling cascade. Evidence from breast and colorectal cancer patient samples have demonstrated a decrease in expression of activin receptor type I, with a concurrent increase in Act A secretion, occurring in a stage- and grade-dependent manner. Additionally, pancreatic cancer cell lines with loss of activin receptor type IB (ALK4) are unresponsive to Act A stimulation, while cells that have intact signaling undergo growth arrest. Preliminary data from our laboratory has demonstrated that dysplastic esophageal squamous cells with intact Act A signaling show less migration, invasion, and proliferation when co-cultured with fibroblasts that stably overexpress Act A, compared to control. However, when esophageal squamous cell carcinoma (ESCC) cells with unaltered Act A signaling are co-cultured long-term with fibroblasts that stably overexpress Act A, the carcinoma cells downregulate ALK4 in response to continious Act A stimulation. As models of ESCC and HNSCC are physiologically similar, we have extrapolated the results we attained regarding the action of Act A in ESCC to HNSCC. Therefore, we hypothesize that loss of cellular responsiveness to Act A through alteration of constituents of the Act A signaling cascade, such as through the downregulation of ALK4, in HNSCC renders the cells insensitive to the growth inhibitory effects of Act A, promoting an invasive cancer phenotype. We will first determine the functional consequences of loss of cellular responsiveness to Act A signaling on HNSCC cell migration and invasion in vitro, using CRISPR-mediated deletion of ALK4 to specifically target Act A signaling. As the tumor microenvironment is critical for cancer progression, we will investigate how disruption of Act A signaling in vivo impacts cancer cell invasion and metastasis. Upon completion of these experiments, we will have determined the nature of Act A signaling in HNSCC and its contribution to cancer progression. Ultimately, these results will aid on the discovery of better diagnostic and prognostic biomarkers for HNSCC.
The proposed research is relevant to public health because the incidence rate of head and neck squamous cell carcinoma is increasing throughout the United States and is often associated with chemotherapeutic resistance and high recurrence rates. The proposed research seeks to identify the prognostic significance of regulatory signaling pathways, in particular Activin A, and how the dysregulation of these pathways contribute to cancer cell invasion and metastasis. This application is relevant to the aspect of the mission of the NIH that pertains to understanding the processes of human growth and development, as well as the causes and diagnosis of human diseases.
| Loomans, Holli A; Arnold, Shanna A; Hebron, Kate et al. (2017) Loss of ACVRIB leads to increased squamous cell carcinoma aggressiveness through alterations in cell-cell and cell-matrix adhesion proteins. Am J Cancer Res 7:2422-2437 |
| Loomans, Holli A; Arnold, Shanna A; Quast, Laura L et al. (2016) Esophageal squamous cell carcinoma invasion is inhibited by Activin A in ACVRIB-positive cells. BMC Cancer 16:873 |
| Loomans, Holli A; Andl, Claudia D (2016) Activin receptor-like kinases: a diverse family playing an important role in cancer. Am J Cancer Res 6:2431-2447 |
