Date of Award

4-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Pharmaceutics

Research Advisor

Subhash C.Chauhan, PhD

Committee

Hassan Almoazen, PhD; Stephen W. Behrman, MD; Clifton Frilot, PhD; Murali M. Yallapu, PhD

Keywords

Atomic force microscopy, chemotherapeutics, MUC13, nanoindentation, Pancreatic cancer

Abstract

Pancreatic adenocarcinoma is one of the deadliest forms of cancer. Even with recent advances in diagnostic tools, chemotherapeutic regimens, and biomarkers for earlier detection, it still has dismal survival rates. Part of the reason for this is the inherent difficulty in detecting and treating this disease. Recent findings suggest that the altered expression of mucins, including MUC13, may be useful molecular signatures for early disease diagnosis, chemotherapy response and predicting patient survival. MUC13, a recently identified transmembrane glycoprotein, is normally associated with forming a protective barrier on epithelial tissues. However, its overexpression/aberrant subcellular localization has been associated with cancer, disease aggressiveness, poorer patient prognosis and drug resistance via alterations of multiple oncogenic signaling pathways. The main objective of this study is to investigate if MUC13 expression influences nanomechanical and biophysical characteristics of pancreatic cancer cells that might contribute to aggressive nature of this disease. To achieve this goal, we performed innovative nanoindentation analyses using atomic force microscopy in conjunction with standard biochemical assays. To combat this malignant disease, multiple approaches have been considered over the years. Recently, a unique biophysical method of cancer detection has been explored in other cancers, whereby an atomic force microscope (AFM) is used to measure the differences in rigidity and adhesion between normal and cancerous cells. AFMs work by using a thin metallic cantilever with a sharp probe which is brought into contact with a sample. Due to the interactions between the probe and the sample, various data can be extracted. AFMs have been used for decades to acquire high resolution, three-dimensional images of a sample, however it is also possible to acquire other types of data. For cancer research, biophysical data can help to differentiate between cancerous cells and their healthy counterparts. Current evidence suggests that normal cells have a greater rigidity than their cancerous counterparts in most malignancies, however literature dealing with pancreatic cancer is limited. In this report, a comprehensive overview of various pancreatic cell lines (both cancerous and non-cancerous) was physically investigated. We noted that there was a significant trend in the reduction of biophysical characteristics associated with differentiation status - namely, poorly differentiated pancreatic cancer cells (MIA PaCa-2, AsPC-1 and Panc-1) have significantly lower rigidity values as compared to moderately differentiated (BxPC-3), well differentiated (HPAF-II) and normal pancreatic epithelia (HPNE). A positive correlation was seen between the adhesion data and aggregation assays - notably, less aggregation was seen in cancer cells as compared to HPNE cells, and

ORCID

https://orcid.org/0000-0001-7688-5501

DOI

10.21007/etd.cghs.2020.0496

Additional Files
2020-005-Massey-DOA.pdf (502 kB)
Declaration of Authorship
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