Andrew E Massey1, Kyle A Doxtater1, Murali M Yallapu2, Subhash C Chauhan3. 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, United States; Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, United States. 2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, United States; Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, United States; South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, United States. 3. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, 38163, United States; Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, United States; South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX, 78504, United States. Electronic address: subhash.chauhan@utrgv.edu.
Abstract
BACKGROUND: Pancreatic cancer is one of the most lethal cancers in the United States. This is partly due to the difficulty in early detection of this disease as well as poor therapeutic responses to currently available regimens. Our previous reports suggest that mucin 13 (MUC13, a transmembrane mucin common to gastrointestinal cells) is aberrantly expressed in this disease state, and has been implicated with a worsened prognosis and an enhanced metastatic potential in PanCa. However, virtually no information currently exists to describe the biophysical ramifications of this protein. METHODS: To demonstrate the biophysical effect of MUC13 in PanCa, we generated overexpressing and knockdown model cell lines for PanCa and subsequently subjected them to various biophysical experiments using atomic force microscopy (AFM) and cellular aggregation studies. RESULTS: AFM-based nanoindentation data showed significant biophysical effects with MUC13 modulation in PanCa cells. The overexpression of MUC13 in Panc-1 cells led to an expected decrease in modulus, and a corresponding decrease in adhesion. With MUC13 knockdown, HPAF-II cells exhibited an increased modulus and adhesion. These results were confirmed with altered cell-cell adhesion as seen with aggregation assays. CONCLUSIONS: MUC13 led to significant biophysical changes in PanCa cells and which exhibited characteristic phenotypic changes in cells demonstrated in previous work from our lab. This work gives insight into the use of biophysical measurements that could be used to help diagnose or monitor cancers as well as determine the effects of genetic alterations at a mechanical level.
BACKGROUND:Pancreatic cancer is one of the most lethal cancers in the United States. This is partly due to the difficulty in early detection of this disease as well as poor therapeutic responses to currently available regimens. Our previous reports suggest that mucin 13 (MUC13, a transmembrane mucin common to gastrointestinal cells) is aberrantly expressed in this disease state, and has been implicated with a worsened prognosis and an enhanced metastatic potential in PanCa. However, virtually no information currently exists to describe the biophysical ramifications of this protein. METHODS: To demonstrate the biophysical effect of MUC13 in PanCa, we generated overexpressing and knockdown model cell lines for PanCa and subsequently subjected them to various biophysical experiments using atomic force microscopy (AFM) and cellular aggregation studies. RESULTS: AFM-based nanoindentation data showed significant biophysical effects with MUC13 modulation in PanCa cells. The overexpression of MUC13 in Panc-1 cells led to an expected decrease in modulus, and a corresponding decrease in adhesion. With MUC13 knockdown, HPAF-II cells exhibited an increased modulus and adhesion. These results were confirmed with altered cell-cell adhesion as seen with aggregation assays. CONCLUSIONS:MUC13 led to significant biophysical changes in PanCa cells and which exhibited characteristic phenotypic changes in cells demonstrated in previous work from our lab. This work gives insight into the use of biophysical measurements that could be used to help diagnose or monitor cancers as well as determine the effects of genetic alterations at a mechanical level.
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