Date Approved

11-2021

Document Type

Dissertation

Degree Name

PhD in Molecular Cell Biology and Neuroscience

Department

Molecular Biology

College

Graduate School of Biomedical Sciences

First Advisor

Gary Goldberg, PhD

Committee Member 1

Kingsley Yin, PhD

Committee Member 2

Ronald Ellis, PhD

Committee Member 3

Robert Nagele, PhD

Committee Member 4

Martin Adelson, PhD

Subject(s)

Intercellular Junctions, Maackia amurensis, Antiviral Agents, Antineoplastic Agents, Cadherins, Podoplanin

Disciplines

Biological Phenomena, Cell Phenomena, and Immunity | Cancer Biology | Medical Cell Biology | Medical Molecular Biology | Medicine and Health Sciences | Molecular Biology | Virology

Abstract

Cells communicate with each other to coordinate tissue function and homeostasis. Diseases including cancer, arthritis, and acute respiratory disease syndrome (ARDS) require a breakdown in this intercellular communication. For example, cancer progression is suppressed by junctional communication between nontransformed and transformed cells. This process is called contact normalization. Junctional communication must be disrupted to enable transformed cells to grow into malignancies. However, the junctions and mechanisms by which nontransformed cells normalize cell behavior have not been clearly defined. My project aimed to identify junctions and elucidate mechanisms underlying contact normalization. We discovered that cadherins, specifically N-cadherin, form junctions that enable nontransformed mouse embryonic cells to normalize the growth of neighboring Src transformed mouse cells and human oral squamous cell carcinoma cells. Previous studies report that the Src kinase phosphorylates the adaptor proteins to induce podoplanin (PDPN) expression in order to promote tumor cell motility and expansion. In this project, we found that PDPN expression enables transformed cells to override contact normalization and proliferate in the face of functional cadherin junctions formed by neighboring nontransformed cells.

Podoplanin is a glycosylated transmembrane receptor containing sialic acid modifications that can be targeted with Maackia amurensis seed lectin (MASL ). MASL is an anti-inflammatory and chemotherapeutic agent that is being examined in an ongoing human clinical trial on oral cancer patients. We performed comprehensive transcriptome analysis to find that MASL modifies the expression of a variety of genes that inhibit inflammation related to arthritis and ARDS, as well as tumor progression. Moreover, we found that MASL can target the sialic acid modified ACE2 receptor which is targeted by the SARS-Co V-2 SI protein to mediate viral infections. Indeed, results from this study indicate that MASL can effectively inhibit SI binding to ACE2 receptor and suppress viral infection of cells that express this receptor.

Taken together, this project: (1) identifies cadherin junctions that mediate contact normalization, (2) finds that the PDPN receptor enables transformed cells to escape this form of growth control, (3) elucidates pathways by which MASL targets the PDPN receptor to inhibit tumor progress, ( 4) finds that MASL can block SI binding to the ACE receptor to inhibit SARS viral infection, and (5) elucidates signaling cascades that MASL affects to reduce inflammation that causes arthritis and COVID-19 instigated ARDS. This project contributes to our understanding of fundamental processes that drive viral infection, cancer, and inflammatory disease, and strategies that can be employed to treat them.

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