Medical Cell Biology Commons^™

Structural Insights Into Cardiolipin Replacement By Phosphatidylglycerol In A Cardiolipin-Lacking Yeast Respiratory Supercomplex, Elena G Govorunova, Oleg A Sineshchekov, Leonid S Brown, Ana-Nicoleta Bondar, John L Spudich

Faculty, Staff and Student Publications

Potassium-selective channelrhodopsins (KCRs) are light-gated K+ channels recently found in the stramenopile protist Hyphochytrium catenoides. When expressed in neurons, KCRs enable high-precision optical inhibition of spiking (optogenetic silencing). KCRs are capable of discriminating K+ from Na+ without the conventional K+ selectivity filter found in classical K+ channels. The genome of H. catenoides also encodes a third paralog that is more permeable for Na+ than for K+. To identify structural motifs responsible for the unusual K+ selectivity of KCRs, we systematically analyzed a series of chimeras and mutants of this protein. We found that mutations of three critical residues in the …

Processing And Cryopreservation Of Human Ureter Tissues For Single-Cell And Spatial Transcriptomics Assays, Emily E Fink, Surbhi Sona, Byron H Lee, Angela H Ting

Faculty, Staff and Student Publications

Characterizing the cellular heterogeneity of human ureter tissues using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics provides a detailed atlas of cell types, signaling networks, and potential cell-cell cross talk underlying developmental and regenerative pathways. We describe an optimized protocol for generating, cryopreserving, and thawing single-cell suspensions from ureter tissues isolated post-cystectomy for scRNA-seq. In addition, we describe an optimized protocol for cryopreserving human ureter tissues for 10x Genomics Visium spatial gene expression platform. For complete details on the use and execution of this protocol, please refer to Fink et al. (2022).

Defining Cellular Population Dynamics At Single-Cell Resolution During Prostate Cancer Progression, Alexandre A Germanos, Sonali Arora, Ye Zheng, Erica T Goddard, Ilsa M Coleman, Anson T Ku, Scott Wilkinson, Hanbing Song, Nicholas J Brady, Robert A Amezquita, Michael Zager, Annalysa Long, Yu Chi Yang, Jason H Bielas, Raphael Gottardo, David S Rickman, Franklin W Huang, Cyrus M Ghajar, Peter S Nelson, Adam G Sowalsky, Manu Setty, Andrew C Hsieh

Faculty, Staff and Student Publications

Advanced prostate malignancies are a leading cause of cancer-related deaths in men, in large part due to our incomplete understanding of cellular drivers of disease progression. We investigate prostate cancer cell dynamics at single-cell resolution from disease onset to the development of androgen independence in an in vivo murine model. We observe an expansion of a castration-resistant intermediate luminal cell type that correlates with treatment resistance and poor prognosis in human patients. Moreover, transformed epithelial cells and associated fibroblasts create a microenvironment conducive to pro-tumorigenic immune infiltration, which is partially androgen responsive. Androgen-independent prostate cancer leads to significant diversification of …

The Rheumatoid Arthritis Drug Auranofin Lowers Leptin Levels And Exerts Antidiabetic Effects In Obese Mice, Aaron R Cox, Peter M Masschelin, Pradip K Saha, Jessica B Felix, Robert Sharp, Zeqin Lian, Yan Xia, Natasha Chernis, David A Bader, Kang Ho Kim, Xin Li, Jun Yoshino, Xin Li, Gang Li, Zheng Sun, Huaizhu Wu, Cristian Coarfa, David D Moore, Samuel Klein, Kai Sun, Sean M Hartig

Faculty, Staff and Student Publications

Low-grade, sustained inflammation in white adipose tissue (WAT) characterizes obesity and coincides with type 2 diabetes mellitus (T2DM). However, pharmacological targeting of inflammation lacks durable therapeutic effects in insulin-resistant conditions. Through a computational screen, we discovered that the FDA-approved rheumatoid arthritis drug auranofin improved insulin sensitivity and normalized obesity-associated abnormalities, including hepatic steatosis and hyperinsulinemia in mouse models of T2DM. We also discovered that auranofin accumulation in WAT depleted inflammatory responses to a high-fat diet without altering body composition in obese wild-type mice. Surprisingly, elevated leptin levels and blunted beta-adrenergic receptor activity achieved by leptin receptor deletion abolished the antidiabetic …

Temporal And Spatial Metabolite Dynamics Impart Control In Adipogenesis, Kristin Eckel-Mahan

Faculty, Staff and Student Publications

The process of adipogenesis is critical for forming new, healthy adipocytes that are capable of storing lipids. In this issue, Sánchez-Ramírez and Ung et al. (2022. J. Cell Biol. https://doi.org/10.1083/jcb.202111137) reveal a novel role for the metabolite nicotinamide adenine dinucleotide in controlling differentiation of mesenchymal stromal cells into adipocytes.

Bcl11b And Atoh8 Coordinate Cellular Plasticity For Reprogramming And Transformation, Mo-Fan Huang, Rachel Shoemaker, Dung-Fang Lee

Faculty, Staff and Student Publications

By dissecting and comparing the transcriptional trajectories and epigenomic traits of reprogramming and transforming cells at the single-cell resolution, Huyghe et al discovered Bcl11b and Atoh8, two key transcription factors controlling cell plasticity during pluripotent reprogramming and oncogenic transformation.

Blockade Of Fgf2/Fgfr2 Partially Overcomes Bone Marrow Mesenchymal Stromal Cells Mediated Progression Of T-Cell Acute Lymphoblastic Leukaemia, Chen Tian, Yueyang Li, Lina Wang, Junqi Si, Yaxin Zheng, Junnan Kang, Yafei Wang, M James You, Guoguang Zheng

Faculty, Staff and Student Publications

The development of acute lymphoblastic leuakemia (ALL) is partly attributed to the effects of bone marrow (BM) microenvironment, especially mesenchymal stromal cells (MSCs), which interact bilaterally with leukaemia cells, leading to ALL progression. In order to find MSCs-based microenvironment targeted therapeutic strategies, Notch1-induced T-cell ALL (T-ALL) mice models were used and dynamic alterations of BM-MSCs with increased cell viability during T-ALL development was observed. In T-ALL mice derived stroma-based condition, leukaemia cells showed significantly elevated growth capacity indicating that MSCs participated in leukaemic niche formation. RNA sequence results revealed that T-ALL derived MSCs secreted fibroblast growth factor 2 (FGF2), which …

The Tumor Invasion Paradox In Cancer Stem Cell-Driven Solid Tumors, Alexandra Shyntar, Ashna Patel, Meghan Rhodes, Heiko Enderling, Thomas Hillen

Faculty, Staff and Student Publications

Cancer stem cells (CSCs) are key in understanding tumor growth and tumor progression. A counterintuitive effect of CSCs is the so-called tumor growth paradox: the effect where a tumor with a higher death rate may grow larger than a tumor with a lower death rate. Here we extend the modeling of the tumor growth paradox by including spatial structure and considering cancer invasion. Using agent-based modeling and a corresponding partial differential equation model, we demonstrate and prove mathematically a tumor invasion paradox: a larger cell death rate can lead to a faster invasion speed. We test this result on a …

Rapid Reconstruction Of Neural Circuits Using Tissue Expansion And Light Sheet Microscopy, Joshua L Lillvis, Hideo Otsuna, Xiaoyu Ding, Igor Pisarev, Takashi Kawase, Jennifer Colonell, Konrad Rokicki, Cristian Goina, Ruixuan Gao, Amy Hu, Kaiyu Wang, John Bogovic, Daniel E Milkie, Linus Meienberg, Brett D Mensh, Edward S Boyden, Stephan Saalfeld, Paul W Tillberg, Barry J Dickson

Faculty, Staff and Student Publications

Brain function is mediated by the physiological coordination of a vast, intricately connected network of molecular and cellular components. The physiological properties of neural network components can be quantified with high throughput. The ability to assess many animals per study has been critical in relating physiological properties to behavior. By contrast, the synaptic structure of neural circuits is presently quantifiable only with low throughput. This low throughput hampers efforts to understand how variations in network structure relate to variations in behavior. For neuroanatomical reconstruction, there is a methodological gulf between electron microscopic (EM) methods, which yield dense connectomes at considerable …

Yap And Taz Promote Osteogenesis And Prevent Chondrogenesis In Neural Crest Cells In Vitro And In Vivo, Xiaolei Zhao, Li Tang, Tram P Le, Bao H Nguyen, Wen Chen, Mingjie Zheng, Hiroyuki Yamaguchi, Brian Dawson, Shuangjie You, Idaliz M Martinez-Traverso, Shannon Erhardt, Jianxin Wang, Min Li, James F Martin, Brendan H Lee, Yoshihiro Komatsu, Jun Wang

Faculty, Staff and Student Publications

Neural crest cells (NCCs) are multipotent stem cells that can differentiate into multiple cell types, including the osteoblasts and chondrocytes, and constitute the majority of the craniofacial skeleton. Here, we show through in vitro and in vivo studies that the transcriptional regulators Yap and Taz have redundant functions as key determinants of the specification and differentiation of NCCs into osteoblasts or chondrocytes. Primary and cultured NCCs deficient in Yap and Taz switched from osteogenesis to chondrogenesis, and NCC-specific deficiency for Yap and Taz resulted in bone loss and ectopic cartilage in mice. Yap bound to the regulatory elements of key …

Artificial Intelligence For Radiation Oncology Applications Using Public Datasets, Kareem A Wahid, Enrico Glerean, Jaakko Sahlsten, Joel Jaskari, Kimmo Kaski, Mohamed A Naser, Renjie He, Abdallah S R Mohamed, Clifton D Fuller

Faculty, Staff and Student Publications

Artificial intelligence (AI) has exceptional potential to positively impact the field of radiation oncology. However, large curated datasets - often involving imaging data and corresponding annotations - are required to develop radiation oncology AI models. Importantly, the recent establishment of Findable, Accessible, Interoperable, Reusable (FAIR) principles for scientific data management have enabled an increasing number of radiation oncology related datasets to be disseminated through data repositories, thereby acting as a rich source of data for AI model building. This manuscript reviews the current and future state of radiation oncology data dissemination, with a particular emphasis on published imaging datasets, AI …

To Bind Or Not To Bind: Cistromic Reprogramming In Prostate Cancer, Michelle Shen, Léa-Kristine Demers, Swneke D Bailey, David P Labbé

Faculty, Staff and Student Publications

The term "cistrome" refers to the genome-wide location of regulatory elements associated with transcription factor binding-sites. The cistrome of key regulatory factors in prostate cancer etiology are substantially reprogrammed and altered during prostatic transformation and disease progression. For instance, the cistrome of the androgen receptor (AR), a ligand-inducible transcription factor central in normal prostate epithelium biology, is directly impacted and substantially reprogrammed during malignant transformation. Accumulating evidence demonstrates that additional transcription factors that are frequently mutated, or aberrantly expressed in prostate cancer, such as the pioneer transcription factors Forkhead Box A1 (FOXA1), the homeobox protein HOXB13, and the GATA binding …

Pim1 Promotes Hepatic Conversion By Suppressing Reprogramming-Induced Ferroptosis And Cell Cycle Arrest, Yangyang Yuan, Chenwei Wang, Xuran Zhuang, Shaofeng Lin, Miaomiao Luo, Wankun Deng, Jiaqi Zhou, Lihui Liu, Lina Mao, Wenbo Peng, Jian Chen, Qiangsong Wang, Yilai Shu, Yu Xue, Pengyu Huang

Faculty, Staff and Student Publications

Protein kinase-mediated phosphorylation plays a critical role in many biological processes. However, the identification of key regulatory kinases is still a great challenge. Here, we develop a trans-omics-based method, central kinase inference, to predict potentially key kinases by integrating quantitative transcriptomic and phosphoproteomic data. Using known kinases associated with anti-cancer drug resistance, the accuracy of our method denoted by the area under the curve is 5.2% to 29.5% higher than Kinase-Substrate Enrichment Analysis. We further use this method to analyze trans-omic data in hepatocyte maturation and hepatic reprogramming of human dermal fibroblasts, uncovering 5 kinases as regulators in the two …

Genetic- And Diet-Induced Ω-3 Fatty Acid Enrichment Enhances Trpv4-Mediated Vasodilation In Mice, Rebeca Caires, Tessa A C Garrud, Luis O Romero, Carlos Fernández-Peña, Valeria Vásquez, Jonathan H Jaggar, Julio F Cordero-Morales

Faculty, Staff and Student Publications

TRPV4 channel activation in endothelial cells leads to vasodilation, while impairment of TRPV4 activity is implicated in vascular dysfunction. Strategies that increase TRPV4 activity could enhance vasodilation and ameliorate vascular disorders. Here, we show that supplementation with eicosapentaenoic acid (EPA), an ω-3 polyunsaturated fatty acid known to have beneficial cardiovascular effects, increases TRPV4 activity in human endothelial cells of various vascular beds. Mice carrying the C. elegans FAT-1 enzyme, which converts ω-6 to ω-3 polyunsaturated fatty acids, display higher EPA content and increased TRPV4-mediated vasodilation in mesenteric arteries. Likewise, mice fed an EPA-enriched diet exhibit enhanced and prolonged TRPV4-dependent vasodilation …

Intermediary Role Of Lung Alveolar Type 1 Cells In Epithelial Repair Upon Sendai Virus Infection, Belinda J Hernandez, Margo P Cain, Anne M Lynch, Jose R Flores, Michael J Tuvim, Burton F Dickey, Jichao Chen

Faculty, Staff and Student Publications

The lung epithelium forms the first barrier against respiratory pathogens and noxious chemicals; however, little is known about how more than 90% of this barrier, made of AT1 (alveolar type 1) cells, responds to injury. Using the Sendai virus to model natural infection in mice, we find evidence that AT1 cells have an intermediary role by persisting in areas depleted of AT2 cells, upregulating IFN responsive genes, and receding from invading airway cells. Sendai virus infection mobilizes airway cells to form alveolar SOX2+ (Sry-box 2+) clusters without differentiating into AT1 or AT2 cells. Large AT2 cell-depleted areas remain covered by …

Schwann Cells Induce Phenotypic Changes In Oral Cancer Cells, Maria Daniela Santi, Morgan Zhang, Elizabeth Salvo, Kesava Asam, Chi T Viet, Tongxin Xie, Moran Amit, Bradley Aouizerat, Yi Ye

Faculty, Staff and Student Publications

Head and neck cancer (HNC) is the seventh most common cancer worldwide, the majority being oral squamous cell carcinoma. Despite advances in cancer diagnosis and treatment, the survival rate of patients with HNC remains stagnant. The cancer-nerve interaction has been recognized as an important driver of cancer progression. Schwann cells, a type of peripheral glia, have been implicated in promoting cancer cell growth, migration, dispersion, and invasion into the nerve in many cancers. Here, it is demonstrated that the presence of Schwann cells makes oral cancer cells more aggressive by promoting their proliferation, extracellular matrix breakdown, and altering cell metabolism. …

Structure-Based Design Of Stapled Peptides That Bind Gabarap And Inhibit Autophagy, Hawley Brown, Mia Chung, Alina Üffing, Nefeli Batistatou, Tiffany Tsang, Samantha Doskocil, Weiqun Mao, Dieter Willbold, Robert C Bast, Zhen Lu, Oliver H Weiergräber, Joshua A Kritzer

Faculty, Staff and Student Publications

The LC3/GABARAP family of proteins is involved in nearly every stage of autophagy. Inhibition of LC3/GABARAP proteins is a promising approach to blocking autophagy, which sensitizes advanced cancers to DNA-damaging chemotherapy. Here, we report the structure-based design of stapled peptides that inhibit GABARAP with nanomolar affinities. Small changes in staple structure produced stapled peptides with very different binding modes and functional differences in LC3/GABARAP paralog selectivity, ranging from highly GABARAP-specific to broad inhibition of both subfamilies. The stapled peptides exhibited considerable cytosolic penetration and resistance to biological degradation. They also reduced autophagic flux in cultured ovarian cancer cells and sensitized …

Twist1 Interacts With Β/Δ-Catenins During Neural Tube Development And Regulates Fate Transition In Cranial Neural Crest Cells, Jessica W Bertol, Shelby Johnston, Rabia Ahmed, Victoria K Xie, Kelsea M Hubka, Lissette Cruz, Larissa Nitschke, Marta Stetsiv, Jeremy P Goering, Paul Nistor, Sally Lowell, Hanne Hoskens, Peter Claes, Seth M Weinberg, Irfan Saadi, Mary C Farach-Carson, Walid D Fakhouri

Faculty, Staff and Student Publications

Cell fate determination is a necessary and tightly regulated process for producing different cell types and structures during development. Cranial neural crest cells (CNCCs) are unique to vertebrate embryos and emerge from the neural plate borders into multiple cell lineages that differentiate into bone, cartilage, neurons and glial cells. We have previously reported that Irf6 genetically interacts with Twist1 during CNCC-derived tissue formation. Here, we have investigated the mechanistic role of Twist1 and Irf6 at early stages of craniofacial development. Our data indicate that TWIST1 is expressed in endocytic vesicles at the apical surface and interacts with β/δ-catenins during neural …

The Intricate Interplay Between Cancer Stem Cells And Cell-Of-Origin Of Cancer: Implications For Therapeutic Strategies, Luis Alberto Vega, Misu A Sanson, María Belén Cubria, Shrijana Regmi, Brittany J Shah, Samuel A Shelburne, Anthony R Flores

Faculty, Staff and Student Publications

Antimicrobial resistance-encoding mobile genetic elements (MGEs) may contribute to the disease potential of bacterial pathogens. We previously described the association of Group A Streptococcus (GAS) derived from invasive disease with increasingly frequent antimicrobial resistance (AMR). We hypothesized that a 65-kb AMR-encoding MGE (ICESpyM92), highly conserved among closely related emergent invasive emm92 GAS, contributes to GAS disease potential. Here, we provide evidence that a combination of ICESpyM92- and core genome-dependent differential gene expression (DGE) contributes to invasive disease phenotypes of emergent emm92 GAS. Using isogenic ICESpyM92 mutants generated in distinct emm92 genomic backgrounds, we determined the presence of ICESpyM92 enhances GAS …

Mettl14-Mediated Epitranscriptome Modification Of Mn1 Mrna Promote Tumorigenicity And All-Trans-Retinoic Acid Resistance In Osteosarcoma, Hong-Bo Li, Gang Huang, Jian Tu, Dong-Ming Lv, Qing-Lin Jin, Jun-Kai Chen, Yu-Tong Zou, Dung-Fang Lee, Jing-Nan Shen, Xian-Biao Xie

Faculty, Staff and Student Publications

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents. The molecular mechanism behind OS progression and metastasis remains poorly understood, which limits the effectiveness of current therapies. RNA N

METHODS: Liquid chromatography-tandem mass spectrometry (LC-MS/MS), dot blotting, and colorimetric ELISA were used to detect m

FINDINGS: We observed the abundance of m

INTERPRETATION: Our study revealed that METTL14 contributes to OS progression and ATRA resistance as an m

FUNDING: This work was supported by the National Natural Science Foundation of China (Grants 81972510 and 81772864).

Adipose Tissue-Specific Ablation Of Ces1d Causes Metabolic Dysregulation In Mice, Gang Li, Xin Li, Li Yang, Shuyue Wang, Yulin Dai, Baharan Fekry, Lucas Veillon, Lin Tan, Rebecca Berdeaux, Kristin Eckel-Mahan, Philip L Lorenzi, Zhongming Zhao, Richard Lehner, Kai Sun

Faculty, Staff and Student Publications

Carboxylesterase 1d (Ces1d) is a crucial enzyme with a wide range of activities in multiple tissues. It has been reported to localize predominantly in ER. Here, we found that Ces1d levels are significantly increased in obese patients with type 2 diabetes. Intriguingly, a high level of Ces1d translocates onto lipid droplets where it digests the lipids to produce a unique set of fatty acids. We further revealed that adipose tissue-specific Ces1d knock-out (FKO) mice gained more body weight with increased fat mass during a high fat-diet challenge. The FKO mice exhibited impaired glucose and lipid metabolism and developed exacerbated liver …

Hematopoietic-Mesenchymal Signals Regulate The Properties Of Mesenchymal Stem Cells, Sanshiro Kanazawa, Hiroyuki Okada, Dan Riu, Yo Mabuchi, Chihiro Akazawa, Junichi Iwata, Kazuto Hoshi, Atsuhiko Hikita

Faculty, Staff and Student Publications

It is well known that the properties of hematopoietic stem/progenitor cells (HSCs), such as their self-renewal ability and multipotency, are maintained through interactions with mesenchymal stem/stromal cells (MSCs). MSCs are rare cells that are present in the bone marrow and are useful for clinical applications due to their functional ability. To obtain the necessary number of cells, MSCs must be cultured to expand, but this causes a remarkable decrease in stem cell properties, such as multipotency and proliferation ability. In this study, we show that the c-Mpl signal, which is related to the maintenance of hematopoietic stem cells, has an …

A Method For Bridging Population-Specific Genotypes To Detect Gene Modules Associated With Alzheimer's Disease, Yulin Dai, Peilin Jia, Zhongming Zhao, Assaf Gottlieb

Faculty, Staff and Student Publications

BACKGROUND: Genome-wide association studies have successfully identified variants associated with multiple conditions. However, generalizing discoveries across diverse populations remains challenging due to large variations in genetic composition. Methods that perform gene expression imputation have attempted to address the transferability of gene discoveries across populations, but with limited success.

METHODS: Here, we introduce a pipeline that combines gene expression imputation with gene module discovery, including a dense gene module search and a gene set variation analysis, to address the transferability issue. Our method feeds association probabilities of imputed gene expression with a selected phenotype into tissue-specific gene-module discovery over protein interaction …

The Use Of Second-Generation Antipsychotics And The Changes In Physical Growth In Children And Adolescents With Perinatally Acquired Hiv, Nan Xin, Jenni Durieux, Chunxia Yang, Suzanne Wolff, Hyun-Eui Kim, Andrew Dillin

Faculty, Staff and Student Publications

The mitochondrial unfolded protein response (UPRmt) is dedicated to promoting mitochondrial proteostasis and is linked to extreme longevity. The key regulator of this process is the transcription factor ATFS-1, which, upon UPRmt activation, is excluded from the mitochondria and enters the nucleus to regulate UPRmt genes. However, the repair proteins synthesized as a direct result of UPRmt activation must be transported into damaged mitochondria that had previously excluded ATFS-1 owing to reduced import efficiency. To address this conundrum, we analyzed the role of the import machinery when the UPRmt was induced. Using in vitro and in vivo analysis of mitochondrial …

Alyref, A Novel Factor Involved In Breast Carcinogenesis, Acts Through Transcriptional And Post-Transcriptional Mechanisms Selectively Regulating The Short Neat1 Isoform, Christiane Klec, Erik Knutsen, Daniela Schwarzenbacher, Katharina Jonas, Barbara Pasculli, Ellen Heitzer, Beate Rinner, Katarina Krajina, Felix Prinz, Benjamin Gottschalk, Peter Ulz, Alexander Deutsch, Andreas Prokesch, Stephan W Jahn, S Mohammad Lellahi, Maria Perander, Raffaela Barbano, Wolfgang F Graier, Paola Parrella, George Adrian Calin, Martin Pichler

Faculty, Staff and Student Publications

The RNA-binding protein ALYREF (THOC4) is involved in transcriptional regulation and nuclear mRNA export, though its role and molecular mode of action in breast carcinogenesis are completely unknown. Here, we identified high ALYREF expression as a factor for poor survival in breast cancer patients. ALYREF significantly influenced cellular growth, apoptosis and mitochondrial energy metabolism in breast cancer cells as well as breast tumorigenesis in orthotopic mouse models. Transcriptional profiling, phenocopy and rescue experiments identified the short isoform of the lncRNA NEAT1 as a molecular trigger for ALYREF effects in breast cancer. Mechanistically, we found that ALYREF binds to the NEAT1 …

Targeting Syndecan-1: New Opportunities In Cancer Therapy, Zecheng Yang, Shuaitong Chen, Haoqiang Ying, Wantong Yao

Faculty, Staff and Student Publications

Syndecan-1 (SDC1, CD138) is one of the heparan sulfate proteoglycans and is essential for maintaining normal cell morphology, interacting with the extracellular and intracellular protein repertoire, as well as mediating signaling transduction upon environmental stimuli. The critical role of SDC1 in promoting tumorigenesis and metastasis has been increasingly recognized in various cancer types, implying a promising potential of utilizing SDC1 as a novel target for cancer therapy. This review summarizes the current knowledge on SDC1 structure and functions, including its role in tumor biology. We also discuss the highlights and limitations of current SDC1-targeted therapies as well as the obstacles …

Dedifferentiation-Mediated Stem Cell Niche Maintenance In Early-Stage Ductal Carcinoma In Situ Progression: Insights From A Multiscale Modeling Study, Joseph D Butner, Prashant Dogra, Caroline Chung, Javier Ruiz-Ramírez, Sara Nizzero, Marija Plodinec, Xiaoxian Li, Ping-Ying Pan, Shu-Hsia Chen, Vittorio Cristini, Bulent Ozpolat, George A Calin, Zhihui Wang

Faculty, Staff and Student Publications

We present a multiscale agent-based model of ductal carcinoma in situ (DCIS) to study how key phenotypic and signaling pathways are involved in the early stages of disease progression. The model includes a phenotypic hierarchy, and key endocrine and paracrine signaling pathways, and simulates cancer ductal growth in a 3D lattice-free domain. In particular, by considering stochastic cell dedifferentiation plasticity, the model allows for study of how dedifferentiation to a more stem-like phenotype plays key roles in the maintenance of cancer stem cell populations and disease progression. Through extensive parameter perturbation studies, we have quantified and ranked how DCIS is …

Development And Characterization Of Anti-Galectin-9 Antibodies That Protect T Cells From Galectin-9-Induced Cell Death, Riyao Yang, Linlin Sun, Ching-Fei Li, Yu-Han Wang, Weiya Xia, Boning Liu, Yu-Yi Chu, Laura Bover, Long Vien, Mien-Chie Hung

Faculty, Staff and Student Publications

Antibodies that target immune checkpoint proteins such as programmed cell death protein 1, programmed death ligand 1, and cytotoxic T-lymphocyte-associated antigen 4 in human cancers have achieved impressive clinical success; however, a significant proportion of patients fail to respond to these treatments. Galectin-9 (Gal-9), a β-galactoside-binding protein, has been shown to induce T-cell death and facilitate immunosuppression in the tumor microenvironment by binding to immunomodulatory receptors such as T-cell immunoglobulin and mucin domain-containing molecule 3 and the innate immune receptor dectin-1, suggesting that it may have potential as a target for cancer immunotherapy. Here, we report the development of two …

Interplay Between Soluble Cd74 And Macrophage-Migration Inhibitory Factor Drives Tumor Growth And Influences Patient Survival In Melanoma, Yasunari Fukuda, Matias A Bustos, Sung-Nam Cho, Jason Roszik, Suyeon Ryu, Victor M Lopez, Jared K Burks, Jeffrey E Lee, Elizabeth A Grimm, Dave S B Hoon, Suhendan Ekmekcioglu

Faculty, Staff and Student Publications

Soluble forms of receptors play distinctive roles in modulating signal-transduction pathways. Soluble CD74 (sCD74) has been identified in sera of inflammatory diseases and implicated in their pathophysiology; however, few relevant data are available in the context of cancer. Here we assessed the composition and production mechanisms, as well as the clinical significance and biological properties, of sCD74 in melanoma. Serum sCD74 levels were significantly elevated in advanced melanoma patients compared with normal healthy donors, and the high ratio of sCD74 to macrophage-migration inhibitory factor (MIF) conferred significant predictive value for prolonged survival in these patients (p = 0.0035). Secretion of …

Genetic Determinants Of Telomere Length From 109,122 Ancestrally Diverse Whole-Genome Sequences In Topmed, Margaret A Taub, Matthew P Conomos, Rebecca Keener, Kruthika R Iyer, Joshua S Weinstock, Lisa R Yanek, John Lane, Tyne W Miller-Fleming, Jennifer A Brody, Laura M Raffield, Caitlin P Mchugh, Deepti Jain, Stephanie M Gogarten, Cecelia A Laurie, Ali Keramati, Marios Arvanitis, Albert V Smith, Benjamin Heavner, Lucas Barwick, Lewis C Becker, Joshua C Bis, John Blangero, Eugene R Bleecker, Esteban G Burchard, Juan C Celedón, Yen Pei C Chang, Brian Custer, Dawood Darbar, Lisa De Las Fuentes, Dawn L Demeo, Barry I Freedman, Melanie E Garrett, Mark T Gladwin, Susan R Heckbert, Bertha A Hidalgo, Marguerite R Irvin, Talat Islam, W Craig Johnson, Stefan Kaab, Lenore Launer, Jiwon Lee, Simin Liu, Arden Moscati, Kari E North, Patricia A Peyser, Nicholas Rafaels, Christine Seidman, Daniel E Weeks, Fayun Wen, Marsha M Wheeler, L Keoki Williams, Ivana V Yang, Wei Zhao, Stella Aslibekyan, Paul L Auer, Donald W Bowden, Brian E Cade, Zhanghua Chen, Michael H Cho, L Adrienne Cupples, Joanne E Curran, Michelle Daya, Ranjan Deka, Celeste Eng, Tasha E Fingerlin, Xiuqing Guo, Lifang Hou, Shih-Jen Hwang, Jill M Johnsen, Eimear E Kenny, Albert M Levin, Chunyu Liu, Ryan L Minster, Take Naseri, Mehdi Nouraie, Muagututi'a Sefuiva Reupena, Ester C Sabino, Jennifer A Smith, Nicholas L Smith, Jessica Lasky Su, James G Taylor, Marilyn J Telen, Hemant K Tiwari, Russell P Tracy, Marquitta J White, Yingze Zhang, Kerri L Wiggins, Scott T Weiss, Ramachandran S Vasan, Kent D Taylor, Moritz F Sinner, Edwin K Silverman, M Benjamin Shoemaker, Wayne H-H Sheu, Frank Sciurba, David A Schwartz, Jerome I Rotter, Daniel Roden, Susan Redline, Benjamin A Raby, Bruce M Psaty, Juan M Peralta, Nicholette D Palmer, Sergei Nekhai, Courtney G Montgomery, Braxton D Mitchell, Deborah A Meyers, Stephen T Mcgarvey, Nhlbi Care Network, Angel Cy Mak, Ruth Jf Loos, Rajesh Kumar, Charles Kooperberg, Barbara A Konkle, Shannon Kelly, Sharon Lr Kardia, Robert Kaplan, Jiang He, Hongsheng Gui, Frank D Gilliland, Bruce D Gelb, Myriam Fornage, Patrick T Ellinor, Mariza De Andrade, Adolfo Correa, Yii-Der Ida Chen, Eric Boerwinkle, Kathleen C Barnes, Allison E Ashley-Koch, Donna K Arnett, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Hematology And Hemostasis Working Group, Topmed Structural Variation Working Group, Cathy C Laurie, Goncalo Abecasis, Deborah A Nickerson, James G Wilson, Stephen S Rich, Daniel Levy, Ingo Ruczinski, Abraham Aviv, Thomas W Blackwell, Timothy Thornton, Jeff O'Connell, Nancy J Cox, James A Perry, Mary Armanios, Alexis Battle, Nathan Pankratz, Alexander P Reiner, Rasika A Mathias

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Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value <5×10-9) in 36 loci associated with telomere length, including 20 newly associated loci (13 were replicated in external datasets). There was little evidence of effect size heterogeneity across populations. Fine-mapping at OBFC1 indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, …