MS, University of Cincinnati, 2024, Medicine: Cancer and Cell Biology

The development and growth of cancer is fundamentally dependent on pro-tumor changes in metabolism. Cancer cells generally shift away from oxidative phosphorylation as the primary source of energy and rely more heavily on glycolysis. Receptor tyrosine kinases (RTKs) are a type of receptor that is implicated in this shift to pro-tumor metabolism. RTKs are important drivers of cancer growth and metastasis. One such family of RTKs is the MET family, which consists of MET and RON(MST1R). The overexpression of either MET or RON has been associated with worse cancer patient prognosis in a variety of tumor types. Both MET and RON signaling promote increased glycolysis by upregulating the expression of key glycolytic enzymes via increased MYC transcription factor activity. Additionally, both MET and RON signaling promote increased cholesterol biosynthesis downstream of glycolysis by upregulating the expression of SREBP2-induced cholesterol biosynthesis enzymes via CTTNB1. These changes in metabolism, driven by RTK activity, provide potential targets in limiting tumor growth and metastasis via pharmacological inhibition or modifications in diet. This review summarizes pro-tumor changes in metabolism driven by the MET family of RTKs. In doing so, we will offer our unique perspective on metabolic pathways that drive worse patient prognosis and provide suggestions for future study.

Committee: Susan Waltz Ph.D. (Committee Chair); Susanne Wells Ph.D. (Committee Member); Amanda Wasylishen Ph.D. (Committee Member) Subjects: Cellular Biology

PhD, University of Cincinnati, 2020, Medicine: Cancer and Cell Biology

Prostate cancer is the second most common cancer in men and the second leading cause of cancer-related deaths in men in the United States, with 191,930 men estimated to be diagnosed with prostate cancer and 33,330 patients expected to succumb to this disease in 2020 alone. Standard-of-care treatments, including active surveillance, surgery, radiation, and androgen deprivation therapy, provide positive clinical outcomes in patients with localized and regional disease. However, these strategies fail to effectively treat advanced prostate cancer, leading to a 5-year survival rate of 31% in patients with distant stage disease. Cancer immunotherapy has emerged as a powerful therapeutic strategy by enhancing the host immune response, particularly cytotoxic CD8+ T cells, to attack tumors. These strategies have proven successful in numerous cancers, such as melanoma, non-small cell lung cancer, and bladder cancer, however prostate cancer remains poorly responsive to these agents. The work presented in this dissertation demonstrates that the RON receptor tyrosine kinase, an oncogene implicated in the tumorigenesis of several epithelial cancers, is a critical regulator of the antitumor immune response in prostate cancer. Our studies herein identify novel RON-mediated communication networks between prostate tumor cells and immune cells as well as between different immune cell populations in the tumor microenvironment. We show that RON signaling in prostate epithelial cells and macrophages supports M2 macrophage activation and modulates the infiltration of multiple immune cell types with known roles in regulating prostate tumor growth and progression, such as CD4+ and CD8+ T cells. Importantly, our studies reveal that loss of RON signaling in macrophages promotes CD8+ T cell activation. Our deeper analyses show that the regulation of M2 macrophage activation by RON is in part through upregulation of RON expression in macrophages. Further, our preliminary data suggest that RON s (open full item for complete abstract)

Committee: Susan Waltz Ph.D. (Committee Chair); George Deepe M.D. (Committee Member); Susan Kasper Ph.D. (Committee Member); David Plas Ph.D. (Committee Member); Kathryn Wikenheiser-Brokamp M.D. (Committee Member) Subjects: Cellular Biology

PhD, University of Cincinnati, 2018, Medicine: Cancer and Cell Biology

Breast cancer is the most common cancer and the second leading cause of cancer-related deaths in women in the United States. Advances in early detection and treatments have improved the outcome of patients with localized/regional disease; however, more than 40,000 patients with aggressive distant breast cancers succumb to this disease each year. This highlights the lack of effectiveness of current treatments in advanced metastatic disease and the need to gain further insight of the mechanisms leading to aggressive breast cancer to develop effective therapies to prevent breast cancer progression and decrease disease mortality. Research on mammary gland development has significantly contributed to understand breast cancer, with cellular processes, cell-to-cell interactions, and pathways important for proper mammary gland development been found deregulated in breast cancer. The RON receptor tyrosine kinase and its ligand HGFL have been recently implicated in breast cancer. However, knowledge of the role of RON and HGFL in regulating mammary gland development and breast cancer progression is limited. Studies presented in this thesis have provided valuable insights that have aided our understanding of the importance and complexity of the HGFL-RON signaling in normal mammary gland development and breast cancer. Studies discussed here have identified novel HGFL-RON-mediated interactions between mammary epithelial cells/tumor cells and cells within the microenvironment that are crucial for proper mammary gland development and breast cancer progression. In addition, studies examining the role of HGFL-RON signaling in mammary gland development provided valuable information about the different cellular compartments where HGFL-RON signaling occurs and led to the studies examining the cell-type specific functions of HGFL-RON signaling in breast cancer progression. Studies discussed in this thesis revealed that activation of HGFL-RON signaling in tumor epithelial cells, breast ca (open full item for complete abstract)

Committee: Susan Waltz Ph.D. (Committee Chair); Jun-Lin Guan Ph.D. (Committee Member); Simon Hogan Ph.D. (Committee Member); Shao-Chun Wang Ph.D. (Committee Member); Susanne Wells Ph.D. (Committee Member) Subjects: Cellular Biology

PhD, University of Cincinnati, 2018, Medicine: Cancer and Cell Biology

Approximately 14% of all men will be diagnosed with prostate cancer. Not only is prostate cancer very prevalent, but as the second leading cause of cancer related deaths in men, it is also very deadly. Many of these deaths result from resistance to androgen deprivation therapy (ADT), defined as Castration Resistant Prostate Cancer (CRPC). The majority of men with CRPC die within 5 years of diagnosis, emphasizing the need for further research for novel CRPC therapeutics. Many prostate cancers become resistant to ADT through reactivation of the Androgen Receptor (AR). Within this dissertation, we demonstrate that the cell surface receptor Ron tyrosine kinase is important in activating AR in prostate cancer under conditions of androgen deprivation, leading to resistance to ADT. Previous studies established the Ron receptor and its ligand (HGFL) as critical players in prostate cancer, with Ron expression levels in prostate cancer correlating with disease severity and loss of Ron or HGFL in the Transgenic Adenocarcinoma of Mouse Prostate model of prostate cancer severely reducing primary tumor growth. These previous studies were critical in demonstrating the importance of Ron in prostate cancer, but had yet to address the potential role of Ron in regulating CRPC. We observed that Ron overexpression was sufficient to drive resistance to castration therapy by overexpressing Ron in androgen sensitive murine and human cell lines for allograft and xenograft models of CRPC. Prostate tumors derived from Ron overexpressing prostate cancer cells display elevated AR activation and require AR to provide growth in androgen depleted conditions. Further, Ron was shown to activate AR in an epithelial cell specific manner through activation of NF-?B and ß-Catenin. As we further analyzed the consequences of Ron overexpression in prostate cancer, we discovered increased macrophage recruitment into Ron overexpressing tumors. We show that macrophage infiltration into Ron overexpressing tum (open full item for complete abstract)

Committee: Susan Waltz Ph.D. (Committee Chair); Fred Finkelman M.D. (Committee Member); Susan Kasper Ph.D. (Committee Member); Joseph Qualls Ph.D. (Committee Member); Shao-Chun Wang Ph.D. (Committee Member) Subjects: Biology

MS, University of Cincinnati, 2016, Medicine: Cancer and Cell Biology

Prostate cancer (PCa) is one of the leading causes of death among men in the United States, particularly given that many patients will present with or develop castration-resistant prostate cancer. Identifying novel biomarkers is therefore essential to develop new therapeutics for the treatment of this disease. While current therapeutics have targeted the androgen receptor, a major driver in the development and progression of PCa, this has been met with limited success. Understanding the role of other potent drivers of PCa is paramount to successful patient outcomes. One potential driver may be the Ron receptor tyrosine kinase. Chronic inflammation has been suggested to be a precursor for the development of PCa and interestingly, Ron has been shown previously to be a regulator of macrophage inflammatory responses. In addition, new studies have suggested its role in oncogenesis. While there are Ron inhibitors in clinical trials for the treatment of several malignancies, there have been no trials looking at Ron inhibition in PCa. Therefore, understanding how Ron functions to mediate inflammatory responses and drive oncogenic events are crucial to potentially utilizing Ron inhibitors for the treatment of prostate cancer.

Committee: Tatiana Kalin M.D.Ph.D. (Committee Chair); Rafeeq Habeebahmed Ph.D. (Committee Member); Atsuo Sasaki Ph.D. (Committee Member) Subjects: Cellular Biology

PhD, University of Cincinnati, 2014, Medicine: Toxicology (Environmental Health)

The vitamin D3 receptor (VDR) is an established negative regulator of mammary gland development and breast cancer as VDR null mice exhibit enhanced epithelial growth during pubertal breast development and are more susceptible to induced carcinogenesis in the mammary gland. Furthermore, the actions of VDR in the breast are largely dependent on the ligand, vitamin D3. However, it is estimated that over 1 billion people worldwide are vitamin D3 deficient or insufficient, including millions of growing children. Despite the alarming number of people with low systemic vitamin D3 levels, little is known about the repercussions of inadequate VDR signaling during critical times of growth and development, such as mammary gland development, and future disease risk. In this dissertation, we studied the cell-type specific contributions of VDR signaling in the breast during mammary gland development and the protective role of VDR in an aggressive form of breast cancer mediated by oncogenic Ron receptor tyrosine kinase overexpression. We show that VDR signaling in both mammary epithelial cells and adipocytes govern ductal outgrowth through the regulation of epithelial cell proliferation and apoptosis within terminal end buds. Mechanistically, adipocytes secrete growth regulatory cytokines such as IL-6 in response to vitamin D3 for VDR-mediated paracrine regulation of epithelial cell fate. In the context of breast cancer, oncogenic Ron is overexpressed in roughly 50% of all human cases. Ron-mediated mammary tumorigenesis requires activation of downstream ß-catenin signaling, which we demonstrate to be antagonized by vitamin D3 through the VDR. Both mammary gland hyperplasia and tumor onset were significantly delayed with VDR signaling and correlated with decreased levels of ß-catenin target genes involved in growth regulation and invasion. Moreover, vitamin D3-dependent VDR signaling increased expression of dickkopf-related protein 1, an extracellular inhibitor of canonical Wnt/ß-c (open full item for complete abstract)

Committee: Shuk-Mei Ho Ph.D. (Committee Chair); Nira Ben-Jonathan Ph.D. (Committee Member); Mary Beth Genter Ph.D. (Committee Member); Susan Kasper Ph.D. (Committee Member); Susan Waltz Ph.D. (Committee Member); Glendon Michael Zinser Ph.D. (Committee Member) Subjects: Developmental Biology

PhD, University of Cincinnati, 2001, Medicine : Environmental Health Sciences

Acute lung injury is a common, severe respiratory syndrome that can develop from indirect and direct insults to the lung. Despite extensive research since the initial description of acute lung injury over 30 years ago, questions remain about the basic pathogenic mechanisms and their relationship to therapeutic strategies. Microarray analysis during the progression of nickel-induced acute lung injury revealed an overall pattern of gene expression consistent with several pathogenic processes, including oxidative stress. NO can generate oxidative stress, either alone or by the formation of other reactive nitrogen species with reactive oxygen species. NO synthesis can be inhibited by binding of hepatocyte growth factor-like protein to the receptor tyrosine kinase Ron. Mice with a targeted deletion of the tyrosine kinase domain of Ron (Ron tk-/-) overproduce NO in response to endotoxin, therefore, these mice were used to examine whether the overproduction of NO would increase susceptibility to nickel-induced acute lung injury. In response to nickel, Ron tk-/- mice displayed decreased survival time, accelerated cytokine expression, augmented serum nitrite levels, and earlier onset of perivascular edema. To examine whether inhibiting NO would increase resistance to nickel-induced acute lung injury, NO synthesis was inhibited using NG-nitro-L-arginine methyl ester (L-NAME). Sixty-percent of L-NAME treated mice survived nickel-induced acute lung injury versus 5% of saline-treated mice. L-NAME treatment attenuated cytokine expression, polymorphonuclear cell infiltration and protein levels in lavage, and restored cyclin dependent kinase like 2 (Cdkl2) and surfactant gene expression. Restoration of surfactant gene expression is consistent with enhanced survival and attenuation of cytokine expression. These findings indicate that Ron is a key regulator of NO during nickel-induced acute lung injury and that NO inhibition may be protective by restoration of surfactant gene express (open full item for complete abstract)

Committee: George Leikauf (Advisor) Subjects:

PhD, University of Cincinnati, 2012, Medicine: Cell and Molecular Biology

The Ron receptor tyrosine kinase is a member of Met family of receptor tyrosine kinases. The ligand for Ron is hepatocyte growth factor like-protein (HGFL). Previous studies from our laboratory have shown that Ron overexpression in the mammary epithelium of mice (referred to as the MMTV-Ron) leads to mammary tumors with hundred percent incidence and were associated with a high degree of metastasis to the lung and liver. Mammary tumors from MMTV-Ron mice exhibit elevated levels of beta-catenin and its target genes. However, the requirement of beta-catenin and HGFL in tumor formation and metastatic dissemination has not been directly examined. We show that Ron and beta-catenin are coordinately elevated in human breast cancers. We also show that Ron activation induces the tyrosine phosphorylation of beta-catenin. HGFL, induced Ron activation leads to beta-catenin nuclear localization and transcriptional activity, with tyrosine residues 654 and 670 of beta-catenin being critical for these processes. We also found that HGFL-dependent Ron activation mediates upregulation of the beta-catenin target genes cyclin D1 and c-myc. Finally, we show that genetic ablation of beta-catenin in Ron-expressing breast cancer cells decreases cellular proliferation in vitro, as well as mammary tumor growth and metastasis following orthotopic transplantation into the mammary fat pad. To determine the significance of HGFL in these processes, we examined mammary tumor growth and metastasis in MMTV-Ron expressing mice with or without a targeted deletion of HGFL. Our studies show that HGFL loss significantly delayed mammary tumor initiation in this model. These changes were associated with a decrease in Ron receptor kinase activity based on kinase assays, and a reduction in mammary tumor proliferation. In addition we show for the first time that HGFL is produced in the tumor microenvironment of MMTV-Ron mice. Also blockade of HGFL, using an HGFL neutralizing antibody decreased mammary tumor gro (open full item for complete abstract)

Committee: Susan Waltz PhD (Committee Chair); George Thomas PhD (Committee Member); Shao-Chun Wang PhD (Committee Member); Susanne Wells PhD (Committee Member); James Wells PhD (Committee Member) Subjects: Molecular Biology

Doctor of Philosophy, The Ohio State University, 2011, Comparative and Veterinary Medicine

Osteosarcoma (OSA) is the most common malignant bone tumor in children and dogs. Currently, 30-40% of children and greater than 90% of dogs succumb to the disease following treatment. The receptor tyrosine kinase (RTK) Met has emerged as a potential target for therapeutic intervention for OSA. Met overexpression in human OSA is associated with a more aggressive phenotype and poor survival, and aberrant expression in normal human osteoblasts induces malignant transformation. The purpose of this work was to evaluate Met as a target for therapeutic intervention in OSA. The first objective was to determine if Met interacts with heat shock protein 90 (Hsp90) in OSA and evaluate a novel Hsp90 inhibitor, STA-1474, for OSA treatment. Hsp90 associated with co-chaperones in canine OSA cells but not normal canine osteoblasts, indicating formation of an active superchaperone complex in malignant versus normal tissue. STA-1474 promoted loss of cell proliferation, apoptosis, and induction of Hsp70. STA-1474 treatment also resulted in the down-regulation of HGF (hepatocyte growth factor) induced p-Met/Met, p-STAT3, and p-Akt/Akt. These data suggest that STA-1474 may be useful for the treatment of OSA. The second objective was to determine whether RTKs Met, epidermal growth factor receptor (EGFR), and Recepteur d'origine nantais (Ron) interact in OSA and explore the functional consequences of such interactions. EGFR and Ron phosphorylation was present in canine OSA tumor tissues, and Met was associated with EGFR and Ron in canine OSA cell lines. High Ron expression was prognostic for survival. Gefitinib (small molecule EGFR inhibitor) and crizotinib (small molecule Met inhibitor) inhibited OSA cell proliferation in an additive manner. Prolonged TGF alpha exposure promoted Met phosphorylation. Co-activation of EGFR and Met with their ligands resulted in amplified ERK1/2 and STAT3 phosphorylation. These data indicate that Met, Ron, and EGFR functionally interact in canine OSA, alter (open full item for complete abstract)

Committee: Cheryl London (Advisor); William Kisseberth (Committee Member); Carlos Alvarez (Committee Member); Ramiro Toribio (Committee Member) Subjects: Oncology

Doctor of Philosophy (PhD), Ohio University, 2007, English (Arts and Sciences)

This study argues that Ron Silliman's Alphabet, an intricate series of book-length poems published during the last three decades, forces readers to analyze connections between form and content. While many contemporary critics have examined Silliman's overall formal constructs, this study focuses on sentence construction—especially on the poet's manipulation of grammar and syntax, his unique punctuation and spelling, and his reliance on indexing—in a number of The Alphabet's early poems. These subversive formal practices constitute the textual practice of parataxis, which Silliman implicitly describes in his critical work The New Sentence as the underlying formal logic of “new sentence” poetry. I argue that Silliman's employment of parataxis creates spaces from which readers may uncover and describe multiple narratives. These narratives reflect and expand Silliman's concern with social issues. The analytical movement in this study reflects its title: I document the formal innovations in the poems that constitute parataxis and open spaces for narratives, and then reach conclusions regarding the works' suggested critiques of certain social and political practices in late-twentieth-century America. The poet, whose activism is well documented, implicitly asks readers to assume an active role in illustrating those critiques. The poems covered in this study—Albany, Blue, Carbon, Demo, Engines, Force, Garfield, Hidden, Ink, Jones, Lit, Manifest, Non, and ®—suggest critiques in several areas where the effects of these practices have been particularly damaging: the environment, technology and new media, academia and publishing, and education and politics. More fundamentally, these poems interrogate the use of language itself; language, after all, motors the social and political practices to which Silliman's work responds. As the study's final chapter argues, Silliman's work is important—and fosters democracy—because it can create the conditions through which active readers ca (open full item for complete abstract)

Committee: George Hartley (Advisor) Subjects: Literature, American

Master of Arts, Miami University, 2004, Theatre

This thesis exists in two parts, practical and written. The practical element was the direction of Ron Elisha's play TWO. The second part is this written thesis, which focuses on developing a critical framework for this play and others of its kind. Included in the written thesis will be an establishment of this critical framework, a structural analysis of Two, and an application of the aforementioned critical framework to the text of Two. Finally, a study of the application of this critical theory from a directorial standpoint will be undertaken, with special attention paid to the use of dramatic action as an expression of the changing nature of religious belief.

Committee: William Doan (Advisor) Subjects: Theater

PhD, University of Cincinnati, 2013, Medicine: Molecular and Cellular Physiology

The Ron receptor tyrosine kinase is an oncogene expressed on epithelial cells and on several tissue resident macrophage populations. Over-expression and/or constitutive activation of Ron have been reported in several epithelial cancers, including prostate cancer. To investigate the significance of Ron expression in prostate cancer our laboratory had examined the loss of function of Ron in the Transgenic Adenocarcinoma of the Mouse Prostate [TRAMP] mouse model. In this model, TRAMP mice crossed with mice that have a germline loss of the tyrosine kinase signaling domain of Ron, referred to as TK-/-, had decreased prostate tumor size when compared to wild type, TK+/+ mice. This study demonstrated the functional importance of Ron signaling in promoting prostate tumor growth; however, the data did not address the selective contributions of Ron signaling in epithelial versus stromal cells during tumorigenesis. Analysis for Ron expression by qRT-PCR showed Ron expression in normal prostate epithelial cells and stromal cells including macrophages. Utilizing human epithelial cell line PC-3, we demonstrated that knockdown of Ron in PC-3 cells leads to decreased prostate tumor growth and metastasis following orthotopic prostate transplantation compared to cells with high Ron expression suggesting that the Ron receptor expressed in epithelial cells is an important factor in prostate tumorigenesis. To test the significance of stromal Ron expression, prostate cancer cells were orthotopically implanted into the prostates of either TK+/+ or TK-/- hosts. In TK-/- hosts, prostate cancer cell growth was significantly reduced compared to controls, suggesting that Ron signaling in the tumor microenvironment is critical to prostate tumor development. Prostate tumors in TK-/- hosts exhibited an increase in tumor cell apoptosis, macrophage infiltration and altered cytokine expression. Reciprocal bone marrow transplantation studies and studies utilizing mice with myeloid cell specific abla (open full item for complete abstract)

Committee: Susan Waltz PhD (Committee Chair); Vladimir Kalinichenko M.D. Ph.D. (Committee Member); David Plas Ph.D. (Committee Member); Shao-Chun Wang Ph.D. (Committee Member); Shao-Chun Wells Ph.D. (Committee Member); Aaron Zorn Ph.D. (Committee Member) Subjects: Oncology

Bachelor of Science of Journalism (BSJ), Ohio University, 2012, Journalism

This study aims to examine cases of newspaper framing that have not been researched exhaustively or in a comparative manner. By using framing to compare cases that involve indicted athletes of various ages and races, this study analyzes content of how newspapers framed athletes amid allegations that they committed violent crimes. This can be accomplished by analyzing media coverage from a common national newspaper and through various newspapers local to the athlete's team or the area where the alleged crime took place. The overarching research question of this study is the following: To what extent do prominence, proximity and orientation affect newspaper framing of indicted U.S. athletes? For the purpose of comparability, only violent crimes that implicate famous athletes, or college athletes attending a prestigious institution, are examined in this study. “Violent crime” is defined as murder, rape or any type of assault or domestic violence. This case examines the 2000 murder indictment of professional football player Ray Lewis of the Baltimore Ravens, the 2006 rape indictment of three members of the Duke University lacrosse team, and the 2004 assault indictment of professional basketball player Ron Artest, who contributed to a brawl between fans and players during a National Basketball Association game between the Detroit Pistons and the Indiana Pacers. The Duke lacrosse case, as mentioned, has drawn some scholarly attention, but Lewis' murder indictment and Artest's assault charge have largely been forgotten, underreported and less researched. That justifies the relevance of this study, which compares collegiate and professional athletes of differing ages and races who have been charged with different types of crimes. Time has elapsed since the criminal proceedings ended, and one of the premises here is that newspapers presented frames that either heavily emphasized or neglected to mention the criminal charges from the last decade.

Committee: Yusuf Kalyango PhD (Advisor); Bernhard Debatin PhD (Committee Chair) Subjects: Communication; Journalism; Mass Communications; Mass Media

Master of Arts (MA), Ohio University, 2012, Art History (Fine Arts)

The performance art practices of Lisa Bufano, Martin O'Brien, and Ron Athey articulate a virtuosic disability that operates in the spaces between representation, embodied experience, and material traces of the diseased or disabled body. Using Gilles Deleuze and Felix Guattari's model of affective, relational bodies, this thesis analyzes Ron Athey's Deliverance and Self-Obliteration cycle, Lisa Bufano's performance work One Breath is an Ocean for a Wooden Heart, and Martin O'Brien's durational performance of Mucus Factory, arguing that when virtuosity and disability are at play with one another in performance, all assumptions about the essential dysfunction of the disabled body become groundless. The disabled body becomes an affirmation of embodiment and possibility, performing a body that can be painful, erotic, sensual, sublime, knowable and unknowable at each turn, opening up the potential for a multiplicity of body knowledges and experiences.

Committee: Jennie Klein PhD (Committee Chair); Jody Lamb PhD (Committee Member); Tresa Randall PhD (Committee Member) Subjects: Art Criticism; Art History; Dance; Fine Arts; Performing Arts