Molecular Biology Commons^™

Cigarette Smoke-Induced Epithelial-To-Mesenchymal Transition: Insights Into Cellular Mechanisms And Signaling Pathways, Sarah Mohammed Alqithami, Amrita Machwe, David K. Orren

Markey Cancer Center Faculty Publications

This review delves into the molecular complexities underpinning the epithelial-to-mesenchymal transition (EMT) induced by cigarette smoke (CS) in human bronchial epithelial cells (HBECs). The complex interplay of pathways, including those related to WNT//β-catenin, TGF-β/SMAD, hypoxia, oxidative stress, PI3K/Akt, and NF-κB, plays a central role in mediating this transition. While these findings significantly broaden our understanding of CS-induced EMT, the research reviewed herein leans heavily on 2D cell cultures, highlighting a research gap. Furthermore, the review identifies a stark omission of genetic and epigenetic factors in recent studies. Despite these shortcomings, the findings furnish a consolidated foundation not only for the …

Nsd3::Nutm1 Fusion Sarcoma Mimicking Malignant Peripheral Nerve Sheath Tumor With Prolonged Survival, Jing Di, Ali M. Alhaidary, Chi Wang, Jinge Liu, Sainan Wei, Joseph Valentino, Therese J. Bocklage

Markey Cancer Center Faculty Publications

Nuclear Protein in Testis (NUT)-rearranged tumors comprise predominantly NUT car- cinoma but also include certain lymphomas, leukemias, skin appendage tumors, and sarcomas. Although histologically diverse, all are genetically identified by oncogenic rearrangement in the NUTM1 gene. Many fusion partners occur, and NSD3 is NUT carcinoma’s third most common partner. Herein, we present a case of a 26-year-old man with an NSD3::NUTM1 fusion sarcoma. The patient presented at the age of 13 months with a scalp nodule. Over the next 24 years, he experienced five local recurrences and ultimately expired of a rapidly progressive recurrence. His treatment included surgical resections, radiation, …

Elevating Plk1 Overcomes Beti Resistance In Prostate Cancer Via Triggering Brd4 Phosphorylation-Dependent Degradation In Mitosis, Yanquan Zhang, Ka-Wing Fong, Fengyi Mao, Ruixin Wang, Derek B. Allison, Dana Napier, Daheng He, Jinpeng Liu, Yeqing Zhang, Jing Chen, Yifan Kong, Chaohao Li, Guangbing Li, Jinghui Liu, Zhiguo Li, Haining Zhu, Chi Wang, Xiaoqi Liu

Markey Cancer Center Faculty Publications

Bromodomain-containing protein 4 (BRD4) has emerged as a promising therapeutic target in prostate cancer (PCa). Understanding the mechanisms of BRD4 stability could enhance the clinical response to BRD4-tar- geted therapy. In this study, we report that BRD4 protein levels are significantly decreased during mitosis in a PLK1-dependent manner. Mechanistically, we show that BRD4 is primarily phosphorylated at T1186 by the CDK1/cyclin B complex, recruiting PLK1 to phosphorylate BRD4 at S24/S1100, which are recognized by the APC/CCdh1 complex for proteasome pathway degradation. We find that PLK1 overexpression lowers SPOP mutation-stabilized BRD4, consequently rendering PCa cells re-sensitized to BRD4 inhibitors. Intrigu-ingly, we …

Soxb1 Transcription Factors Are Essential For Initiating And Maintaining Neural Plate Border Gene Expression, Elizabeth Schock, Joshua R. York, Austin P. Li, Ashlyn Y. Tu, Carole Labonne

Markey Cancer Center Faculty Publications

SoxB1 transcription factors (Sox2/3) are well known for their role in early neural fate specification in the embryo, but little is known about functional roles for SoxB1 factors in non-neural ectodermal cell types, such as the neural plate border (NPB). Using Xenopus laevis, we set out to determine whether SoxB1 transcription factors have a regulatory function in NPB formation. Here, we show that SoxB1 factors are necessary for NPB formation, and that prolonged SoxB1 factor activity blocks the transition from a NPB to a neural crest state. Using ChIP-seq, we demonstrate that Sox3 is enriched upstream of NPB genes in …

Response To Replication Stress And Maintenance Of Genome Stability By Wrn, The Werner Syndrome Protein, David K. Orren, Amrita Machwe

Markey Cancer Center Faculty Publications

Werner syndrome (WS) is an autosomal recessive disease caused by loss of function of WRN. WS is a segmental progeroid disease and shows early onset or increased frequency of many characteristics of normal aging. WRN possesses helicase, annealing, strand exchange, and exonuclease activities and acts on a variety of DNA substrates, even complex replication and re- combination intermediates. Here, we review the genetics, biochemistry, and probably physiological functions of the WRN protein. Although its precise role is unclear, evidence suggests WRN plays a role in pathways that respond to replication stress and maintain genome stability particularly in telomeric regions.

Effect Of Plumbagin On Chemo-Resistant Metastatic Retinoblastoma, John J. Soto

Theses and Dissertations

Retinoblastoma, which is an ocular malignancy, usually results in poor prognoses in pediatric patients worldwide. Retinoblastoma in some events, can develop metastatic phenotypes which can lead to secondary tumor formation, furthering deleterious patient outcomes. It is of paramount importance to identify and research potent novel compounds that can be used to increase the likelihood of remission. Plumbagin (PLB) is a plant-derived, neuroprotective agent, which exhibits significant anticancer activities during in vitro study. PLB has been shown to have a high therapeutic efficacy against chemoresistant sublines as well as their normal counterparts. We attempted to show that the chemoresistant ABCC1 could …

Single-Cell Analysis Identifies Plk1 As A Driver Of Immunosuppressive Tumor Microenvironment In Luad, Yifan Kong, Chaohao Li, Jinpeng Liu, Sai Wu

Markey Cancer Center Faculty Publications

PLK1 (Polo-like kinase 1) plays a critical role in the progression of lung adenocarcinoma (LUAD). Recent studies have unveiled that targeting PLK1 improves the efficacy of immuno- therapy, highlighting its important role in the regulation of tumor immunity. Nevertheless, our understanding of the intricate interplay between PLK1 and the tumor microenvironment (TME) remains incomplete. Here, using genetically engineered mouse model and single- cell RNA-seq analysis, we report that PLK1 promotes an immunosuppressive TME in LUAD, characterized with enhanced M2 polarization of tumor associated macrophages (TAM) and dampened antigen presentation process. Mechanistically, elevated PLK1 coin- cides with increased secretion of CXCL2 …

Unveiling The Nexus Of Cellular Quality Control: Exploring The Interplay Between Ribosome-Associated Protein Quality Control And Mitochondrial Quality Control Pathways, Foozhan Tahmasebinia

Biological Sciences Theses and Dissertations

In eukaryotic cells, the intricate interplay between cellular quality control mechanisms is crucial for maintaining homeostasis and safeguarding the integrity of vital processes, spanning from macromolecule synthesis to the renewal of entire cellular organelles.

Disruption of these networks can lead to severe diseases such as metabolic disorders, underscoring the interconnected nature and feedback control mechanisms inherent in biological systems, including cellular quality control systems. This interconnectedness extends to the intricate communication between organelles, enabling coordinated functioning and adaptation to changing cellular conditions, particularly in response to stressors.

While the exact mechanisms governing these communications within cellular quality control systems remain …

Protein Oxidation In Aging And Alzheimer’S Disease Brain, Rukhsana Sultana, D. Allan Butterfield

Markey Cancer Center Faculty Publications

Proteins are essential molecules that play crucial roles in maintaining cellular homeostasis and carrying out biological functions such as catalyzing biochemical reactions, structural proteins, immune response, etc. However, proteins also are highly susceptible to damage by reactive oxygen species (ROS) and reactive nitrogen species (RNS). In this review, we summarize the role of protein oxidation in normal aging and Alzheimer’s disease (AD). The major emphasis of this review article is on the carbonylation and nitration of proteins in AD and mild cognitive impairment (MCI). The oxidatively modified proteins showed a strong correlation with the reported changes in brain structure, carbohydrate …

Predicting The Pathway Involvement Of Metabolites Based On Combined Metabolite And Pathway Features, Erik D. Huckvale, Hunter N. B. Moseley

Markey Cancer Center Faculty Publications

A major limitation of most metabolomics datasets is the sparsity of pathway annotations for detected metabolites. It is common for less than half of the identified metabolites in these datasets to have a known metabolic pathway involvement. Trying to address this limitation, machine learning models have been developed to predict the association of a metabolite with a “pathway category”, as defined by a metabolic knowledge base like KEGG. Past models were implemented as a single binary classifier specific to a single pathway category, requiring a set of binary classifiers for generating the predictions for multiple pathway categories. This past approach …

Predictive And Prognostic Biomarkers And Tumor Antigens For Targeted Therapy In Urothelial Carcinoma, Aditya Eturi, Amman Bhasin, Kevin Zarrabi, William Tester

Department of Medical Oncology Faculty Papers

Urothelial carcinoma (UC) is the fourth most prevalent cancer amongst males worldwide. While patients with non-muscle-invasive disease have a favorable prognosis, 25% of UC patients present with locally advanced disease which is associated with a 10-15% 5-year survival rate and poor overall prognosis. Muscle-invasive bladder cancer (MIBC) is associated with about 50% 5 year survival when treated by radical cystectomy or trimodality therapy; stage IV disease is associated with 10-15% 5 year survival. Current therapeutic modalities for MIBC include neoadjuvant chemotherapy, surgery and/or chemoradiation, although patients with relapsed or refractory disease have a poor prognosis. However, the rapid success of …

Discovery Of A Small-Molecule Inhibitor That Traps Polθ On Dna And Synergizes With Parp Inhibitors, William Fried, Mrityunjay Tyagi, Leonid Minakhin, Gurushankar Chandramouly, Taylor Tredinnick, Mercy Ramanjulu, William Auerbacher, Marissa L Calbert, Timur Rusanov, Trung Hoang, Nikita Borisonnik, Robert Betsch, John Krais, Yifan Wang, Umeshkumar Vekariya, John Gordon, George Morton, Tatiana Kent, Tomasz Skorski, Neil Johnson, Wayne Childers, Xiaojiang Chen, Richard Pomerantz

Department of Biochemistry and Molecular Biology Faculty Papers

The DNA damage response (DDR) protein DNA Polymerase θ (Polθ) is synthetic lethal with homologous recombination (HR) factors and is therefore a promising drug target in BRCA1/2 mutant cancers. We discover an allosteric Polθ inhibitor (Polθi) class with 4-6 nM IC₅₀ that selectively kills HR-deficient cells and acts synergistically with PARP inhibitors (PARPi) in multiple genetic backgrounds. X-ray crystallography and biochemistry reveal that Polθi selectively inhibits Polθ polymerase (Polθ-pol) in the closed conformation on B-form DNA/DNA via an induced fit mechanism. In contrast, Polθi fails to inhibit Polθ-pol catalytic activity on A-form DNA/RNA in which the enzyme binds in …

Myeloid-Derived Suppressor Cell Mitochondrial Fitness Governs Chemotherapeutic Efficacy In Hematologic Malignancies, Saeed Daneshmandi, Jee Eun Choi, Qi Yan, Cameron R. Macdonald, Manu Pandey, Mounika Goruganthu, Nathan Roberts, Prashant K. Singh, Richard M. Higashi, Andrew N. Lane, Teresa W-M Fan, Jianmin Wang, Philip L. Mccarthy, Elizabeth A. Repasky, Hemn Mohammadpour

Markey Cancer Center Faculty Publications

Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprogram- ing, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of …

Remodeling Anaplastic Thyroid Cancer's Aggressive Profile And Metabolic Signature By Natural Alkaloid Berberine, Tara Elizabeth Jarboe

NYMC Student Theses and Dissertations

Anaplastic thyroid cancer is a rare, fatal cancer with a five-year survival of 4%. Universally diagnosed at stage IV, anaplastic thyroid cancer is characterized by its lack of differentiation, rapid proliferative rate, highly inflammatory tumor microenvironment, and metabolic dysregulation. Refractory to all established therapies, anaplastic thyroid cancer requires a novel therapeutic approach that targets all of these drivers of anaplastic thyroid cancer carcinogenesis. We propose natural alkaloid berberine as a therapeutic with multitarget efficacy to alter mitochondrial metabolism and reprogram anaplastic thyroid cancer’s aggressive phenotype. Our in vitro model uses monocyte cell line U937, anaplastic thyroid cancer cell lines T238 …

Androgen Drives Melanoma Invasiveness And Metastatic Spread By Inducing Tumorigenic Fucosylation, Qian Liu

USF Tampa Graduate Theses and Dissertations

Melanoma incidence and mortality rates are historically higher for men than women, with an estimated ~47% more new cases and twice the lethality in men in the US in 2023. Consistent with these discrepancies, emerging studies have highlighted the tumorigenic role of the male sex hormone androgen and its receptor (AR) in promoting melanoma aggressiveness. However, underlying cellular and molecular mechanisms and their precise pathological contributions are not well-defined. We recently discovered a sex-associated disparity in melanoma fucosylation, the post-translational modification of proteins with the dietary sugar L-fucose. Fucosylation, the conjugation of fucose moieties onto different glycan linkages on target …

Cold-Inducible Rna Binding Protein Impedes Breast Tumor Growth In The Pymt Murine Model For Breast Cancer, Daniel A. Lujan, Joey L. Ochoa, Ellen J. Beswick, Tamara A. Howard, Helen J. Hathaway, Nora I. Perrone-Bizzozero, Rebecca S. Hartley

Markey Cancer Center Faculty Publications

RNA binding proteins (RBPs) post-transcriptionally regulate gene expression by associating with regulatory sequences in the untranslated regions of mRNAs. Cold-inducible RBP (CIRP) is a stress-induced RBP that was recently shown to modulate inflammation in response to cellular stress, where it increases or decreases pro-tumorigenic (proinflammatory) cytokines in different contexts. CIRP expression is altered in several cancers, including breast cancer, but the effects of CIRP on inflammation in breast cancer is not known. Here, we investigate if CIRP alters growth and the inflammatory profile of breast tumors. Transgenic mice overexpressing CIRP in the mammary epithelium were crossed with the PyMT mouse …

The Carboxy Terminus Causes Interfacial Assembly Of Oleate Hydratase On A Membrane Bilayer, Christopher D. Radka, Christy R. Grace, Hale S. Hasdemir, Yupeng Li, Carlos C. Rodriguez, Patrick Rodrigues, Michael L. Oldham, M. Zuhaib Qayyum, Aaron Pitre, William J. Maccain, Ravi C. Kalathur, Emad Tajkhorshid, Charles O. Rock

Markey Cancer Center Faculty Publications

The soluble flavoprotein oleate hydratase (OhyA) hydrates the 9-cis double bond of unsaturated fatty acids. OhyA sub- strates are embedded in membrane bilayers; OhyA must remove the fatty acid from the bilayer and enclose it in the active site. Here, we show that the positively charged helix- turn-helix motif in the carboxy terminus (CTD) is responsible for interacting with the negatively charged phosphatidylgly- cerol (PG) bilayer. Super-resolution microscopy of Staphylo- coccus aureus cells expressing green fluorescent protein fused to OhyA or the CTD sequence shows subcellular localization along the cellular boundary, indicating OhyA is membrane- associated and the CTD sequence …

Strategies For Improving The Performance Of Prediction Models For Response To Immune Checkpoint Blockade Therapy In Cancer, Tiantian Zeng, Jason Z. Zhang, Arnold Stromberg, Jin Chen, Chi Wang

Markey Cancer Center Faculty Publications

Immune checkpoint blockade (ICB) therapy holds promise for bringing long-lasting clinical gains for the treatment of cancer. However, studies show that only a fraction of patients respond to the treatment. In this regard, it is valu- able to develop gene expression signatures based on RNA sequencing (RNAseq) data and machine learning meth- ods to predict a patient’s response to the ICB therapy, which contributes to more personalized treatment strategy and better management of cancer patients. However, due to the limited sample size of ICB trials with RNAseq data available and the vast number of candidate gene expression features, it is …

Vaginal Lactobacillus Fatty Acid Response Mechanisms Reveal A Metabolite-Targeted Strategy For Bacterial Vaginosis Treatment, Paul C. Blainey, Seth M. Bloom, Douglas S. Kwon

Markey Cancer Center Faculty Publications

Bacterial vaginosis (BV), a common syndrome characterized by Lactobacillus-deficient vaginal microbiota, is associated with adverse health outcomes. BV often recurs after standard antibiotic therapy in part because antibiotics promote microbiota dominance by Lactobacillus iners instead of Lactobacillus crispatus, which has more beneficial health associations. Strategies to promote L. crispatus and inhibit L. iners are thus needed. We show that oleic acid (OA) and similar long-chain fatty acids simultaneously inhibit L. iners and enhance L. crispatus growth. These phenotypes require OA-inducible genes conserved in L. crispatus and related lactobacilli, including an oleate hydratase (ohyA) and putative fatty acid efflux pump (farE). …

Elevated Free Cholesterol Levels Due To Impaired Reverse Cholesterol Transport Are A Risk Factor For Polymicrobial Sepsis In Mice, Qian Wang, Ling Guo, Dan Hao, Misa Ito, Chieko Mineo, Philip W. Shaul, Xiang-An Li

Markey Cancer Center Faculty Publications

Dysregulated lipid metabolism is commonly observed in septic patients, but how it contributes to sepsis remains largely unknown. Reverse cholesterol transport (RCT) is crucial for regulating cholesterol metabolism in circulation. During RCT, high-density lipoprotein collects cholesterol from peripheral tissues and transports it to the liver’s scavenger receptor BI (SR- BI), where SR-BI mediates the uptake of cholesteryl esters (CEs) from high-density lipoprotein for excretion via bile. In this study, we utilized AlbCreSR-BIfl/fl mice, a model with impaired RCT, to investigate the impact of RCT on sepsis. We found that AlbCreSR-BIfl/fl mice were significantly more susceptible to cecal ligation and puncture …

Therapeutic Potential Of Berberine In Attenuating Cholestatic Liver Injury: Insights From A Psc Mouse Model, Yanyan Wang, Derrick Zhao, Lianyong Su, Yun-Ling Tai, Grayson W. Way, Jing Zeng, Qianhua Yan, Ying Xu, Xuan Wang, Emily C. Gurley, Xi-Qiao Zhou, Jinze Liu, Jinpeng Liu, Weidong Chen, Philip B. Hylemon, Huiping Zhou

Markey Cancer Center Faculty Publications

Background and aims

Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by progressive biliary inflammation and bile duct injury. Berberine (BBR) is a bioactive isoquinoline alkaloid found in various herbs and has multiple beneficial effects on metabolic and inflammatory diseases, including liver diseases. This study aimed to examine the therapeutic effect of BBR on cholestatic liver injury in a PSC mouse model (Mdr2 −/− mice) and eluci‑ date the underlying mechanisms.

Methods

Mdr2−/− mice (12–14 weeks old, both sexes) received either BBR (50 mg/kg) or control solution daily for eight weeks via oral gavage. Histological and serum biochemical …

Mechanisms Of Γδ T Cell Accumulation In Visceral Adipose Tissue With Aging, Sujata Mukherjee, Maria E. C. Bruno, Jason Oakes, Gregory S. Hawk, Arnold Stromberg, Donald A. Cohen, Marlene E. Starr

Markey Cancer Center Faculty Publications

γδ T cells are resident in visceral adipose tissue (VAT) where they show an age- associated increase in numbers and contribute to local and systemic chronic inflammation. However, regulation of this population and mechanisms for the age-dependent accumulation are not known. In this study, we identified a progressive trend of γδ T cell accumulation in VAT over the lifespan in mice and explored physiological mechanisms contributing to accumulation. Using isochronic parabiotic pairs of wild-type (WT) and T cell receptor delta knockout (TCRδ KO) mice at young and old age, we confirmed that VAT γδ T cells are predominately a tissue-resident …

A Novel Protozoa Parasite-Derived Protein Adjuvant Is Effective In Immunization With Cancer Cells To Activate The Cancer-Specific Protective Immunity And Inhibit The Cancer Growth In A Murine Model Of Colorectal Cancer, Rajesh Mani, Chloe G. Martin, Kanal E. Balu, Qingding Wang, Piotr G. Rychahou, Tadahide Izumi, B. Mark Evers, Yasuhiro Suzuki

Markey Cancer Center Faculty Publications

Cancer-specific CD8+ cytotoxic T cells play important roles in preventing cancer growth, and IFN-γ, in addition to IL-12 and type I interferon, is critical for activating CD8+ cytotoxic T cells. We recently identified the capability of the amino-terminus region of dense granule protein 6 (GRA6Nt) of Toxoplasma gondii, an intracellular protozoan parasite, to activate IFN-γ production of microglia, a tissue-resident macrophage population. Therefore, in the present study, we examined whether recombinant GRA6Nt protein (rGRA6Nt) functions as an effective adjuvant to potently activate cancer-specific protective immunity using a murine model of MC38 colorectal cancer (CRC). When mice were immunized with non-replicable …

Structure, Dynamics, And Redox Reactivity Of An All-Purpose Flavodoxin, Sharique Khan, Ahmadullah Ansari, Monica Brachi, Debarati Das, Wassim El Housseini, Shelley Minteer, Anne-Francis Miller

Markey Cancer Center Faculty Publications

The flavodoxin of Rhodopseudomonas palustris CGA009 (Rp9Fld) supplies highly reducing equivalents to crucial en- zymes such as hydrogenase, especially when the organism is iron-restricted. By acquiring those electrons from photodriven electron flow via the bifurcating electron transfer flavoprotein, Rp9Fld provides solar power to vital metabolic processes. To understand Rp9Fld’s ability to work with diverse partners, we solved its crystal structure. We observed the canonical fla- vodoxin (Fld) fold and features common to other long-chain Flds but not all the surface loops thought to recognize part- ner proteins. Moreover, some of the loops display alternative structures and dynamics. To advance studies …

Non-Transcriptional Irf7 Interacts With Nf-Κb To Inhibit Viral Inflammation, Shumin Fan, Sonam Popli, Sukanya Chakravarty, Ritu Chakravarty, Saurabh Chattopadhyay

Markey Cancer Center Faculty Publications

Interferon (IFN) regulatory factors (IRF) are key transcrip- tion factors in cellular antiviral responses. IRF7, a virus- inducible IRF, expressed primarily in myeloid cells, is required for transcriptional induction of interferon α and antiviral genes. IRF7 is activated by virus-induced phosphory- lation in the cytoplasm, leading to its translocation to the nu- cleus for transcriptional activity. Here, we revealed a nontranscriptional activity of IRF7 contributing to its antiviral functions. IRF7 interacted with the pro-inflammatory tran- scription factor NF-κB-p65 and inhibited the induction of in- flammatory target genes. Using knockdown, knockout, and overexpression strategies, we demonstrated that IRF7 inhibited NF-κB–dependent inflammatory …

Foxs1 Is Increased In Liver Fibrosis And Regulates Tgfβ Responsiveness And Proliferation Pathways In Human Hepatic Stellate Cells, Evelyn A. Bates, Zachary A. Kipp, Wang-Hsin Lee, Genesee J. Martinez, Lauren Weaver, Kathryn N. Becker, Sally Pauss, Justin F. Creeden, Garrett B. Anspach, Robert N. Helsley, Mei Xu, Maria E. C. Bruno, Marlene E. Starr, Terry D. Hinds Jr.

Markey Cancer Center Faculty Publications

Liver fibrosis commences with liver injury stimulating transforming growth factor beta (TGFβ) activation of hepatic stellate cells (HSCs), causing scarring and irreversible damage. TGFβ induces expression of the transcription factor Forkhead box S1 (FOXS1) in hepatocytes and may have a role in the pathogenesis of hepatocellular carcinoma (HCC). To date, no studies have determined how it affects HSCs. We analyzed human livers with cirrhosis, HCC, and a murine fibrosis model and found that FOXS1 expression is significantly higher in fibrotic livers but not in HCC. Next, we treated human LX2 HSC cells with TGFβ to activate fibrotic pathways, and FOXS1 …

A Novel Role Of Tgfbi In Macrophage Polarization And Macrophage-Induced Pancreatic Cancer Growth And Therapeutic Resistance, Jing Zhou, Nan Lyu, Qiongling Wanga, Ming Yang, Eric T. Kimchi, Kun Chenge, Trupti Joshi, Adama R. Tukulif, Kevin F. Staveley-O’Carroll, Guangfu Li

Biomedical Sciences

Tumor-associated macrophages (TAMs), as a major and essential component of tumor microenvironment (TME), play a critical role in orchestrating pancreatic cancer (PaC) tumorigenesis from initiation to angiogenesis, growth, and systemic dissemination, as well as immunosuppression and resistance to chemotherapy and immunotherapy; however, the critical intrinsic factors responsible for TAMs reprograming and function remain to be identified. By performing single-cell RNA sequencing, transforming growth factor-beta-induced protein (TGFBI) was identified as TAM-producing factor in murine PaC tumors. TAMs express TGFBI in human PaC and TGFBI expression is positively related with human PaC growth. By inducing TGFBI loss-of-function in macrophage (MΦs) in vitro …

Cell Aggregation Activates Small Gtpase Rac1 And Induces Cd44 Cleavage By Maintaining Lipid Raft Integrity, Dong Li, Younhee Park, Hami Hemati, Xia Liu

Markey Cancer Center Faculty Publications

Lipid rafts are highly ordered membrane domains that are enriched in cholesterol and glycosphingolipids and serve as major platforms for signal transduction. Cell detachment from the extracellular matrix (ECM) triggers lipid raft disruption and anoikis, which is a barrier for cancer cells to metastasize. Compared to single circulating tumor cells (CTCs), our recent studies have demonstrated that CD44-mediatd cell aggregation enhances the stemness, survival and metastatic ability of aggregated cells. Here, we investigated whether and how lipid rafts are involved in CD44-mediated cell aggregation. We found that cell detachment, which mimics the condition when tumor cells detach from the ECM …

Cyclin D1 Extensively Reprograms Metabolism To Support Biosynthetic Pathways In Hepatocytes, Heng Wu, Betsy T. Kren, Andrew N. Lane, Teresa A. Cassel, Richard M. Higashi, Teresa Whei-Mei Fan, George S. Scaria, Laurie L. Shekels, Mark A. Klein, Jeffrey H. Albrecht

Markey Cancer Center Faculty Publications

Cell proliferation requires metabolic reprogramming to accommodate biosynthesis of new cell components, and similar alterations occur in cancer cells. However, the mechanisms linking the cell cycle machinery to metabolism are not well defined. Cyclin D1, along with its main partner cyclindependent kinase 4 (Cdk4), is a pivotal cell cycle regulator and driver oncogene that is overexpressed in many cancers. Here, we examine hepatocyte proliferation to define novel effects of cyclin D1 on biosynthetic metabolism. Metabolomic studies reveal that cyclin D1 broadly promotes biosynthetic pathways including glycolysis, the pentose phosphate pathway, and the purine and pyrimidine nucleotide synthesis in hepatocytes. Proteomic …

Md_Harmonize: A Python Package For Atom-Level Harmonization Of Public Metabolic Databases, Huan Jin, Hunter N. B. Moseley

Markey Cancer Center Faculty Publications

A major challenge to integrating public metabolic resources is the use of different nomenclatures by individual databases. This paper presents md_harmonize, an open-source Python package for harmonizing compounds and metabolic reactions across various metabolic databases. The md_harmonize package utilizes a neighborhood-specific graph coloring method for generating a unique identifier for each compound via atom identifiers based on a compound’s chemical structure. The resulting harmonized compounds and reactions can be used for various downstream analyses, including the construction of atom-resolved metabolic networks and models for metabolic flux analysis. Parts of the md_harmonize package have been optimized using a variety of computational …