UMD Theses and Dissertations
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Item UNDERSTANDING FUNCTIONAL BEHAVIORS OF ORGANOTROPIC TRIPLE NEGATIVE BREAST CANCER CELLS(2023) DeCastro, Ariana Joy; Stroka, Kimberly M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)11.7% of all cancer cases consist of breast cancer worldwide according to global cancer statistics. Triple negative breast cancer (TNBC) is subtype of breast cancer that has no expression of common hormonal receptors - estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Due to this, TNBC is insensitive to endocrine or molecular targeted therapy and chemotherapy is the most effective treatment. Additionally, TNBC patients have reoccurrence within 3 years of diagnosis. Going further, due to the non-specific targeting of chemotherapy, cancer cells can develop drug resistance. The gold standard does not work in conjunction with microenvironmental factors to reduce disease progression and drug resistance. Not only is this disease lacking in effective treatments but is associated with a health disparity being most prevalent in pre-menopausal and African American women. There is clearlya need to understand the mechanisms of TNBC metastasis because of the impact not only on women in general but on women in historically marginalized communities. A significant innovation in determining cancer treatment is the use of genomic sequencing to identify mutations associated with metastasis. However, tumor heterogeneity puts limitations on fully understanding genomic landscape of TNBC, a highly mutational disease, using sequencing. Further, even when mutations are identified they may not be targetable, or patients may not respond to treatments. While genomic sequencing can be beneficial in improving treatment outcomes, they require further downstream validation of genetic expression to completely understand tumor biology and metastatic progression. This is where understanding the functional behavior of tumor cells with respect to their preferred secondary microenvironment can be advantageous in supplementing genomics data to get a comprehensive understanding of TNBC metastasis. The overall goal of this dissertation is to address this gap by quantifying tumor cell functional behavior and their response to microenvironmental cues. We evaluate three different physical and biochemical behaviors of TNBC tumor cells. In Chapter 3, the effect of TNBC secretome on endothelial barrier properties and function is explored. Chapter 4 quantifies the morphological and migratory phenotypes of brain and bone-seeking TNBC cells in response to ECM protein substrates found in their relevant microenvironments. Lastly, Chapter 5 will quantify the TNBC incorporation in response to brain relevant microenvironmental cues. Quantifying these functional behaviors could provide indicators of brain and bone tropic metastatic behavior and have broader impacts in creating a complete physical profile of organotropic TNBC metastasis.Item THE ROLE OF THE MECHANICAL ENVIRONMENT ON CANCER CELL TRANSMIGRATION AND MRNA LOCALIZATION(2016) Hamilla, Susan M.; Aranda-Espinoza, Helim; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Most cancer-related deaths are due to metastasis formation, the ability of cancer cells to break away from the primary tumor site, transmigrate through the endothelium, and form secondary tumors in distant areas. Many studies have identified links between the mechanical properties of the cellular microenvironment and the behavior of cancer cells. Cells may experience heterogeneous microenvironments of varying stiffness during tumor progression, transmigration, and invasion into the basement membrane. In addition to mechanical factors, the localization of RNAs to lamellipodial regions has been proposed to play an important part in metastasis. This dissertation provides a quantitative evaluation of the biophysical effects on cancer cell transmigration and RNA localization. In the first part of this dissertation, we sought to compare cancer cell and leukocyte transmigration and investigate the impact of matrix stiffness on transmigration process. We found that cancer cell transmigration includes an additional step, ‘incorporation’, into the endothelial cell (EC) monolayer. During this phase, cancer cells physically displace ECs and spread into the monolayer. Furthermore, the effects of subendothelial matrix stiffness and endothelial activation on cancer cell incorporation are cell-specific, a notable difference from the process by which leukocytes transmigrate. Collectively, our results provide mechanistic insights into tumor cell extravasation and demonstrate that incorporation into the endothelium is one of the earliest steps. In the next part of this work, we investigated how matrix stiffness impacts RNA localization and its relevance to cancer metastasis. In migrating cells, the tumor suppressor protein, adenomatous polyposis coli (APC) targets RNAs to cellular protrusions. We observed that increasing stiffness promotes the peripheral localization of these APC-dependent RNAs and that cellular contractility plays a role in regulating this pathway. We next investigated the mechanism underlying the effect of substrate stiffness and cellular contractility. We found that contractility drives localization of RNAs to protrusions through modulation of detyrosinated microtubules, a network of modified microtubules that associate with, and are required for localization of APC-dependent RNAs. These results raise the possibility that as the matrix environment becomes stiffer during tumor progression, it promotes the localization of RNAs and ultimately induces a metastatic phenotype.Item THE POTENTIAL DICHOTOMOUS ROLE OF ACTIVATING TRANSCRIPTION FACTOR 3 (ATF3) IN COLON CANCER(2015) Jiang, Xiaojing; Lee, Seong-Ho; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Colorectal cancer (CRC) is the third leading cause of cancer-related death in the United States. During the tumorigenesis and metastasis of CRC, cells encounter numerous cellular and molecular events. ATF3, a member of the ATF/CREB transcription factor family, plays an important role on regulation of apoptosis and is regarded as a potential molecular target for chemoprevention and chemotherapy of colon cancer. The current study was performed to investigate cellular and molecular mechanisms by which ATF3 affects colon cancer-related phenotypes including apoptosis and metastasis. Here, we demonstrated that knockdown of ATF3 using small interfering RNA (siRNA) promotes the expression of anti-apoptotic protein, B-cell lymphoma 2 (Bcl-2), in colon cancer cells, while overexpression of ATF3 resulted in a dramatic decrease in Bcl-2 protein. Gain of function of ATF3 in colon cancer cell line HCT116 led to an increase of pro-apoptotic protein Bcl-2 homologous antagonist killer (Bak), followed by the induction of apoptosis. Furthermore, we observed that ATF3 overexpression downregulated expression of epithelial-mesenchymal transition (EMT)-related transcription factors. However, mammosphere forming assay indicated that ATF3 overexpressed colon cancer cells form larger and more budding sites compared to control, which is associated with an increase of cluster of differentiation 44 (CD44) expression and a decrease of retinoblastoma (Rb) and tight junction protein zonula occludens (ZO)-1. This study suggested that ATF3 may play a dichotomous role in regulation of apoptosis and metastasis in colon cancer.