Cancer Biology Commons^™

Synthesis Of Novel 5-Aryl 2’-Deoxyuridine And 2’-Deoxycytidine Analogues, Kevin E. Persaud

Dissertations and Theses

Briefly, the following report details a synthetic route to prepare 5-phenyl-2’-deoxycytidine analogues. This multistep synthesis began with silyl protection of the 3’- and 5’-hydroxyl groups of 5-iodo-2’-deoxyuridine. Next, the installation of a phenyl ring at the C5 position of the nucleobase via a Suzuki-Miyaura cross-coupling reaction, yielding 5-phenyl-2’-deoxyuridine (5-PdU). After that, modification of the obtained 5-PdU at the C4 position was performed with benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP, a peptide-coupling agent) and a base (cesium carbonate) to activate the amide group of the uridine nucleobase for subsequent displacement with a variety of amines. Modification of the C4 position resulted in protected 5-phenyl-2’-deoxycytidine …

Investigating The Regulation Of Epithelial-Mesenchymal Transition Through Fibronectin-Mediated Tgf-Β1 Mechanotransduction Using In Vitro Models Of Triple-Negative Breast Cancer, Michael M. Sofroniou

Theses and Dissertations

TGF-β1 is a potent regulator of epithelial-mesenchymal transtion (EMT), a cellular
transdifferentation process that promotes cellular motility and matrix remodeling, critical to tumorigenesis and metastasis. TGF-β1-induced EMT promotes the assembly of FN, which synergistically binds latent TGF-β1 to aid in its activation. The purpose of of this work is to further probe the effects of autocrine TGF-β1 signaling during EMT progression by utilizing CRISPR-Cas9 deletion of the TGFB1 gene in in vitro models of triple-negative breast cancer. The studies outlined in this work demonstrate that autocrine TGF-β1 maintains a baseline level of mesenchymal marker expression. It also functions to desensitize …

Elucidating The Role Of Sialic Acid In Tumorigenic Pathways, Kakali Das

Electronic Theses and Dissertations

Hypersialylation is a prognostic biomarker in cancer cells. The upregulated sialic acid expression on cancer cells facilitates tumorigenesis by playing a critical role in cancer cell proliferation and growth, immune evasion, cell signaling, and metastasis by interacting with various carbohydrate-binding molecules. Sialic acids on cancer cell surface undergo various modifications like O-acetylation at positions 4,7,9 de-acetylation and addition of glycolyl group at position 5. In our first chapter we analyzed the effect of de-acetylated sialic acid on migration via selectin binding in colon cancer cell line HCT116 and in lung cancer cell line A549. Selectins are calcium-dependent cell adhesion molecules …

A Scoping Review Of Population Diversity In The Common Genomic Aberrations Of Clear Cell Renal Cell Carcinoma, Sean S. Kumar, Ninad Khandekar, Komal Dani, Saina R. Bhatt, Vinay Duddalwar, Anishka D'Souza

Department of Medicine Faculty Publications

Introduction: Previous literature has shown that clear cell renal cell carcinoma (ccRCC) is becoming a more prevalent diagnosis and that the incidence and mortality differ both regionally and racially. While the molecular profiles for ccRCC are studied regionally through biopsy and sequencing techniques, the genomic landscape and ccRCC diversity data are not well-studied. We conducted a review of the known genomic data on 6 of the most clinically relevant DNA biomarkers in ccRCC: Von Hippel-Landau (vHL), Polybromo-1 (PBRM1), Breast Cancer Gene 1-Associated Protein 1 (BAP1), Histone-Lysine N-Methyltransferase Domain-Containing 2 (SETD2), Mammalian Target of Rapamycin (mTOR), and Lysine-Specific Demethylase 5C (KDM5C). …

Plk1 Overexpression Drives Tumorigenesis In A Prostate Cancer Mouse Model, Emile Kachouh

Theses and Dissertations

Prostate cancer is the leading cause of cancer-related deaths among men worldwide, and the development of resistance to existing treatments necessitates the exploration of new therapeutic strategies, including combination therapies. This study investigates the role of Polo-like kinase 1 (PLK1), located on chromosome 16p12.2, as an oncogene in prostate cancer. We generated a transgenic mouse model with prostate-specific overexpression of PLK1 to closely mimic human prostate cancer progression. Quantitative PCR (qPCR) analysis was employed to characterize the molecular profile of PLK1, revealing its implication in multiple pathways. To further elucidate the functional consequences of PLK1 overexpression, we confirmed phenotypic progression …

Chromatin Regulation By Swi/Snf Remodelers In Somatic Stem Cell Maintenance And Transformation, Luke Thomas Deary

Dartmouth College Ph.D Dissertations

Cell identity is defined by the epigenome, whereby chromatin regulators work in concert to promote gene expression programs that serve a cell’s specialized purpose. Mutations in chromatin regulators are amongst the most frequent drivers of human disease, underscoring the importance of understanding their activities in maintaining cell identity and tissue function. In particular, mutations in subunits of the evolutionarily conserved SWI/SNF chromatin remodeling complexes drive diseases across human tissues in both development and adult tissue maintenance5. Three major SWI/SNF complexes exist: BAF, PBAF, and GBAF, which differ in their composition and genomic targeting but share an ATP-dependent catalytic activity to …

Sccad: Cluster Decomposition-Based Anomaly Detection For Rare Cell Identification In Single-Cell Expression Data, Yunpei Xu, Shaokai Wang, Qilong Feng, Jiazhi Xia, Yaohang Li, Hong-Dong Li, Jianxin Wang

Computer Science Faculty Publications

Single-cell RNA sequencing (scRNA-seq) technologies have become essential tools for characterizing cellular landscapes within complex tissues. Large-scale single-cell transcriptomics holds great potential for identifying rare cell types critical to the pathogenesis of diseases and biological processes. Existing methods for identifying rare cell types often rely on one-time clustering using partial or global gene expression. However, these rare cell types may be overlooked during the clustering phase, posing challenges for their accurate identification. In this paper, we propose a Cluster decomposition-based Anomaly Detection method (scCAD), which iteratively decomposes clusters based on the most differential signals in each cluster to effectively separate …

Triphlapan: Predicting Hla Molecules Binding Peptides Based On Triple Coding Matrix And Transfer Learning, Meng Wang, Chuqi Lei, Jianxin Wang, Yaohang Li, Min Li

Computer Science Faculty Publications

Human leukocyte antigen (HLA) recognizes foreign threats and triggers immune responses by presenting peptides to T cells. Computationally modeling the binding patterns between peptide and HLA is very important for the development of tumor vaccines. However, it is still a big challenge to accurately predict HLA molecules binding peptides. In this paper, we develop a new model TripHLApan for predicting HLA molecules binding peptides by integrating triple coding matrix, BiGRU + Attention models, and transfer learning strategy. We have found the main interaction site regions between HLA molecules and peptides, as well as the correlation between HLA encoding and binding …

Identifying New Cancer Genes Based On The Integration Of Annotated Gene Sets Via Hypergraph Neural Networks, Chao Deng, Hong-Dong Li, Li-Shen Zhang, Yiwei Liu, Yaohang Li, Jianxin Wang

Computer Science Faculty Publications

Motivation

Identifying cancer genes remains a significant challenge in cancer genomics research. Annotated gene sets encode functional associations among multiple genes, and cancer genes have been shown to cluster in hallmark signaling pathways and biological processes. The knowledge of annotated gene sets is critical for discovering cancer genes but remains to be fully exploited.

Results

Here, we present the DIsease-Specific Hypergraph neural network (DISHyper), a hypergraph-based computational method that integrates the knowledge from multiple types of annotated gene sets to predict cancer genes. First, our benchmark results demonstrate that DISHyper outperforms the existing state-of-the-art methods and highlight the advantages of …

Paper-Based Dna Biosensor For Rapid And Selective Detection Of Mir-21, Alexander Hunt, Sri Ramulu Torati, Gymama Slaughter

Electrical & Computer Engineering Faculty Publications

Cancer is the second leading cause of death globally, with 9.7 million fatalities in 2022. While routine screenings are vital for early detection, healthcare disparities persist, highlighting the need for equitable solutions. Recent advancements in cancer biomarker identification, particularly microRNAs (miRs), have improved early detection. MiR-21 is notably overexpressed in various cancers and can be a valuable diagnostic tool. Traditional detection methods, though accurate, are costly and complex, limiting their use in resource-limited settings. Paper-based electrochemical biosensors offer a promising alternative, providing cost-effective, sensitive, and rapid diagnostics suitable for point-of-care use. This study introduces an innovative electrochemical paper-based biosensor that …

Methylene Blue-Mediated Photodynamic Therapy In Combination With Doxorubicin: A Novel Approach In The Treatment Of Ht-29 Colon Cancer Cells, Nima Rastegar-Pouyani, Jaber Zafari, Alireza Nasirpour, Hossein Vazini, Nabbaa Najjar, Seyedeh Zohreh Azarshin, Fatemeh Javani Jouni

Electrical & Computer Engineering Faculty Publications

Introduction: With an alarmingly growing number of patients diagnosed with colorectal cancer, adopting innovative anti-cancer approaches has recently garnered great attention. One interesting concept is the co-administration of cytotoxic agents and safer modalities such as photodynamic therapy (PDT), which can subsequently improve therapeutic efficacy and potentially reduce the risks of severe adverse effects and drug resistance. In the course of PDT, a locally injected photosensitizer (PS) is irradiated with a light source, which subsequently generates reactive oxygen species (ROS) and induces programmed cell death in tumor cells.

Methods: In this study, to evaluate the potential anti-cancer effects of chemotherapy combined …

Estrogen Receptor (Er) Alpha Regulatory Mechanisms And Therapeutic Strategies In Er+ Breast Cancer, Bianca A. Romo

Dartmouth College Ph.D Dissertations

Breast cancer is among the most frequently diagnosed cancers in the U.S. and is one of the leading causes of cancer-related mortalities, second to lung cancer. Estrogen receptor alpha-positive (ER+) breast cancer accounts for 2/3 of diagnosed cases. Patients diagnosed with this subtype of breast cancer typically undergo endocrine therapy that aims to mitigate the growth-promoting effects of estrogen/ER. While therapies are effective, 1/3 of patients will experience recurrence. To begin addressing this drug-resistant patient population, we investigated potential drug targets involved in response to treatment.

Coregulators have been implicated in the regulation of ER transcriptional activity and subsequently affecting …

Desmoglein-2 As A Cancer Modulator: Friend Or Foe?, Kay Myo Min, Charlie Ffrench, Barbara Mcclure, Michael Ortiz, Emma Dorward, Michael Samuel, Lisa Ebert, Mỹ Mahoney, Claudine Bonder

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Desmoglein-2 (DSG2) is a calcium-binding single pass transmembrane glycoprotein and a member of the large cadherin family. Until recently, DSG2 was thought to only function as a cell adhesion protein embedded within desmosome junctions designed to enable cells to better tolerate mechanical stress. However, additional roles for DSG2 outside of desmosomes are continuing to emerge, particularly in cancer. Herein, we review the current literature on DSG2 in cancer and detail its impact on biological functions such as cell adhesion, proliferation, migration, invasion, intracellular signaling, extracellular vesicle release and vasculogenic mimicry. An increased understanding of the diverse repertoire of the biological …

27-Hydroxycholesterol And Dna Damage Repair: Implication In Prostate Cancer, Gloria Cecilia Galvan, Nadine Friedrich, Sanjay Das, James Daniels, Sara Pollan, Shweta Dambal, Ryusuke Suzuki, Sergio Sanders, Sungyong You, Hisashi Tanaka, Yeon-Joo Lee, Wei Yuan, Johann De Bono, Irina Vasilevskaya, Karen Knudsen, Michael Freeman, Stephen Freedland

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

INTRODUCTION: We previously reported that cholesterol homeostasis in prostate cancer (PC) is regulated by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, is frequently lost in PCs. We observed that restoring the CYP27A1/27HC axis inhibited PC growth. In this study, we investigated the mechanism of 27HC-mediated anti-PC effects.

METHODS: We employed in vitro models and human transcriptomics data to investigate 27HC mechanism of action in PC. LNCaP (AR+) and DU145 (AR-) cells were treated with 27HC or vehicle. Transcriptome profiling was performed using the Affymetrix GeneChip™ microarray system. Differential expression was determined, and gene set enrichment …

Needle Biopsy Accelerates Pro-Metastatic Changes And Systemic Dissemination In Breast Cancer: Implications For Mortality By Surgery Delay, Hiroyasu Kameyama, Priya Dondapati, Reese Simmons, Macall Leslie, John Langenheim, Yunguang Sun, Misung Yi, Aubrey Rottschaefer, Rashmi Pathak, Shreya Nuguri, Kar-Ming Fung, Shirng-Wern Tsaih, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

ncreased breast cancer (BC) mortality risk posed by delayed surgical resection of tumor after diagnosis is a growing concern, yet the underlying mechanisms remain unknown. Our cohort analyses of early-stage BC patients reveal the emergence of a significantly rising mortality risk when the biopsy-to-surgery interval was extended beyond 53 days. Additionally, histology of post-biopsy tumors shows prolonged retention of a metastasis-permissive wound stroma dominated by M2-like macrophages capable of promoting cancer cell epithelial-to-mesenchymal transition and angiogenesis. We show that needle biopsy promotes systemic dissemination of cancer cells through a mechanism of sustained activation of the COX-2/PGE₂/EP2 feedforward loop, …

Melittin: A Natural Component Of Honeybee Venom As A Potential Anti-Cancer Therapy, Niamh Donnellan, Anne M. Friel

SURE Journal: Science Undergraduate Research Experience Journal

Cancer is a major cause of death worldwide and while chemotherapy is the main approach there are many negative associations in current treatment procedures. These include lack of selectivity, side effects and drug resistance. The hallmarks of cancer are a fundamental concept which aids the development of new means to treat human cancers through the understanding of the acquisition of these hallmarks from cells.

Melittin is a major peptide component of bee venom which has shown to be efficacious as an anticancer agent in preclinical and animal models. Melittin has many biological functions including pore formation in the phospholipid bilayer …

Characterization Of Trafficking And Metabolic Functions Of The Endocytic Regulator Ehd1 In Ewing Sarcoma, Sukanya Chakraborty

Theses & Dissertations

Ewing sarcoma (EWS) is the second most common bone malignancy in children and adolescents. Despite improvement in survival due to advances in multimodality treatment strategies, patients with metastatic or recurrent disease have very poor outcomes. Overexpression of the EPS15 Homology Domain containing 1 (EHD1) protein has been linked to tumorigenesis but whether its core function as a regulator of intracellular traffic of cell surface receptors plays a role in oncogenesis remains unknown.

Studies presented in this dissertation establish that EHD1 overexpression is a feature of nearly 90% EWS patient tumors with high EHD1 expression specifying shorter patient survival. ShRNA-knockdown and …

Role Of The Ganglioside Gd2 And Its Biosynthetic Enzyme Gd3 Synthase In Prostate Cancer Tumorigenesis, Aaqib Bhat

Theses & Dissertations

Despite significant advancements in managing localized prostate cancer (PC), which have notably increased survival rates, advanced PC continues to be a leading cause of cancer- related fatalities. The discovery of new pathways that can be targeted to inhibit tumor growth in PC could pave the way for innovative treatment strategies. The disialylganglioside GD2 is an FDA-approved target for antibody therapies in neuroblastoma and has not been extensively studied in the context of PC. The work done in this thesis reveals that GD2 is present on a minor subset of PC cells in certain patients and is more prevalent in metastatic …

Pediatric Parosteal Osteosarcoma Of The Distal Radius Causing Extensive Erosive Mass Effect Of The Adjacent Ulna: A Case Report, Andrea Perloff, Sehoon Park, Robert Panganiban, John Devries

Department of Orthopaedics Faculty Research

Introduction: Parosteal osteosarcomas are low-grade bony malignancies that are treated primarily with surgical resection and reconstruction. This report discusses a unique case of a pediatric patient who presented with a parosteal osteosarcoma of the distal radius causing extensive erosive mass effect and growth disturbance of the adjacent ulna. Likely due to their slow-growing nonaggressive nature, parosteal osteosarcomas have not been previously described to abut adjacent bony structures through direct contact. The patient presented in a significantly delayed manner due to social circumstances, inadvertently revealing this novel behavior. This report reviews this rare case and describes the current understanding of this …

Phi-1, An Endogenous Inhibitor Protein For Protein Phosphatase-1 And A Pan-Cancer Marker, Regulates Raf-1 Proteostasis, Jason Kirkbride, Garbo Nilsson, Jee In Kim, Kosuke Takeya, Yoshinori Tanaka, Hiroshi Tokumitsu, Futoshi Suizu, Masumi Eto

Kimmel Cancer Center Faculty Papers

Raf-1, a multifunctional kinase, regulates various cellular processes, including cell proliferation, apoptosis, and migration, by phosphorylating MAPK/ERK kinase and interacting with specific kinases. Cellular Raf-1 activity is intricately regulated through pathways involving the binding of regulatory proteins, direct phosphorylation, and the ubiquitin-proteasome axis. In this study, we demonstrate that PHI-1, an endogenous inhibitor of protein phosphatase-1 (PP1), plays a pivotal role in modulating Raf-1 proteostasis within cells. Knocking down endogenous PHI-1 in HEK293 cells using siRNA resulted in increased cell proliferation and reduced apoptosis. This heightened cell proliferation was accompanied by a 15-fold increase in ERK1/2 phosphorylation. Importantly, the observed …