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Evaluating the Role of Heterogenous Mechanical Forces on Lung Cancer Development and Screening

Cho, YouJin
http://orcid.org/0000-0001-8952-5193
http://rave.ohiolink.edu/etdc/view?acc_num=osu1619135551701767

Abstract Details

2021, Doctor of Philosophy, Ohio State University, Biomedical Engineering.
Lung cancer is leading cause of cancer-related deaths in the United States with 5-year survival rate of 18.6%. This is due to late detection of lung cancer and problems in screening for lung cancer. Indeterminate pulmonary nodules (IPNs) are pulmonary nodules size between 7-20mm diameter solid nodules. 90% of IPNs are incidentally found and they are hard to diagnosis due to their small size and current diagnosis methods such as CT, PET scans and biopsy involve high exposure to radiation or invasive and could lead to complications. The majority of lung cancer patients have non-small cell lung cancer (NSCLC) and 64% of these patients exhibit driver mutations such as epithelial growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and Ras mutations. These patients have shown to have improved survival rate if they are treated with targeted therapies directed against the driver mutations. Although these patients initially show strong response to targeted therapies, most patients develop resistance to these targeted treatments through secondary point mutation and epithelial to mesenchymal transition (EMT). The lung is a dynamic organ where alveolar epithelial cells are normally exposed to significant mechanical forces (i.e. ~8% cyclic strain, transmural pressure and shear stress) while primary lung tumor cells experience a 40-fold decrease in these mechanical forces/strain. Although biomechanical factors in the tumor microenvironment have been shown to be a significant driver of cancer progression, there is limited information about how biophysical forces alters drug sensitivity in lung adenocarcinoma cells. Based on the known importance of mechanical forces/strain on lung injury and repair and the significant difference in cyclic strain applied to normal and cancer cells in the lung, we hypothesized that cyclic mechanical strain would activate important oncogenic pathways and alter drug sensitivity. Although local mechanical properties of the lung tumor may be an important prognostic factor, there is currently no way to non-invasively assess local lung mechanical properties. Magnetic resonance electrography (MRE) is a non-invasive imaging technique that uses shear wave propagation to measure mechanical stiffness of soft tissues. Dr. Kolipaka’s lab has developed an MRE protocol that can measure temporally and spatially varying changes in lung tissue stiffness from normal adults. Furthermore, MRE has been used to quantify a 3-fold increase in lung tissue stiffness in fibrotic patients compared to normal controls. However, MRE has not been used to evaluate the stiffness profile of tumors within in lung cancer patients. Therefore, in this study, we test the hypothesis that the mechanical forces present within lung tumor microenvironment plays an important role in tumor progression and therapeutic response. Based on this hypothesis, we propose to 1) define different biophysical forces present in lung tumor microenvironment 2) investigate role of biomechanical forces in drug response and migratory behavior on the lung adenocarcinoma cells in-vitro and 3) verify and identify the biomechanical forces in patients with using the non-invasive imaging (i.e. MRE) and finite element modeling (FEM). The overall goal of this study is to both obtain a better understanding of how dynamic biomechanical forces in the lung tumor microenvironment affect tumorigenesis and therapeutic response and to establish a clinically-relevant methodology to non-invasively assess local tumor mechanical properties in patients with IPN. Using finite element modeling of idealized lung model with tumor, the study have shown that the there are heterogeneous strains and stresses present – low strain in stiff center of tumor, high strain and strain gradient in the peritumoral region. Using this a novel in-vitro system was developed to deliver non-uniform deformation. Our study has shown that high strain and strain gradient led to increase in migration and increase in response to drug therapy. Furthermore, in this study, novel non-invasive technique was developed using MRE and FEM. This technique highlighted the importance of the heterogeneity spatial stiffness is important in characterizing strain magnitude and spatial strain gradient in normal, CF and IPN patients.
Ghadiali Samir, Dr. (Advisor)
Joshua Englert, Dr. (Committee Member)
Arunark Kolipaka, Dr. (Committee Member)
140 p.
Biomedical Engineering
lung cancer; biomechanics; stretching; migration; finite element modeling; finite element modeling of lung; cystic fibrosis; magnetic resonance elastography; indeterminate pulmonary nodules; lung cancer screening;

Recommended Citations

Citations

  • Cho, Y. (2021). Evaluating the Role of Heterogenous Mechanical Forces on Lung Cancer Development and Screening [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1619135551701767

    APA Style (7th edition)

  • Cho, YouJin. Evaluating the Role of Heterogenous Mechanical Forces on Lung Cancer Development and Screening. 2021. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1619135551701767.

    MLA Style (8th edition)

  • Cho, YouJin. "Evaluating the Role of Heterogenous Mechanical Forces on Lung Cancer Development and Screening." Doctoral dissertation, Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu1619135551701767

    Chicago Manual of Style (17th edition)

osu1619135551701767
274
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