Medical Cell Biology Commons^™

Investigation Of The Dyrk1a Regulation By Lzts2-Sipa1l1 Complex, Rebecca Gunnin, Austin Witt B.S., Larisa Litovchick M.D.,Ph.D.

Undergraduate Research Posters

A region on chromosome 21, the Down Syndrome critical region (DSCR), is associated with major defects found in Down Syndrome, such as craniofacial malformations. DYRK1A is a gene found on chromosome 21 within the DSCR that encodes an enzyme, dual specificity tyrosine-phosphorylation-regulated kinase 1A. DYRK1A is known to phosphorylate many substrate proteins and is thought to be involved in tumor suppression, neurological development, cell cycle regulation, and aging. Recently, the Litovchick lab and others reported that DYRK1A also plays a role in the double-strand break repair of DNA, which could lead to mutations and tumorigenesis, if deregulated.

The Litovchick lab …

Characterizing The Effects Of Antiandrogens And Senolytics To Enhance The Therapeutic Response To Castration-Resistant Prostate Cancer, Justin M. Silverman

Theses and Dissertations

Prostate cancer is the most frequently diagnosed cancer in males and the second most common cause of cancer deaths. Androgen deprivation therapy, whether through surgical or chemical castration, is the mainstay for treatment of advanced prostate cancer; however, despite an initial response, most patients eventually develop a progressive PSA rise, and castration- sensitive prostate cancer gives rise to castration-resistant prostate cancer. The standard of care therapy includes the antiandrogens such as enzalutamide and abiraterone acetate as well as the microtubule poison, docetaxel, and various immunotherapies; however, while prostate cancer research is progressing, there continues to be a compelling need for …

Role Of Adenosine Deaminase In Prostate Cancer Progression, Christy Charles, Stacy M Lloyd, Danthasinghe Waduge Badrajee Piyarathna, Jie Gohlke, Uttam Rasaily, Vasanta Putluri, Brian W Simons, Alexander Zaslavsky, Srinivas Nallandhighal, George Michailidis, Nallasivam Palanisamy, Nora Navone, Jeffrey A Jones, Michael M Ittmann, Nagireddy Putluri, David R Rowley, Simpa S Salami, Ganesh S Palapattu, Arun Sreekumar

Faculty, Staff and Students Publications

Prostate cancer (PCa) is the second most common cancer and constitutes about 14.7% of total cancer cases. PCa is highly prevalent and more aggressive in African-American (AA) men than in European-American (EA) men. PCa tends to be highly heterogeneous, and its complex biology is not fully understood. We use metabolomics to better understand the mechanisms behind PCa progression and disparities in its clinical outcome. Adenosine deaminase (ADA) is a key enzyme in the purine metabolic pathway; it was found to be upregulated in PCa and is associated with higher-grade PCa and poor disease-free survival. The inosine-to-adenosine ratio, which is a …

Molecular Mechanisms Of Prdm16 As A Tumor Suppressor In Pancreatic Ductal Adenocarcinoma, Eric Hurwitz

Theses and Dissertations

The transcription factor Prdm16 functions as a potent suppressor of transforming growth factor-beta (TGF-b) signaling, whose inactivation is deemed essential to the progression of pancreatic ductal adenocarcinoma (PDAC). Using the Kras^G12D-based mouse model of human PDAC, we surprisingly found that ablating Prdm16 did not block but instead accelerated PDAC formation and progression, suggesting that Prdm16 might function as a tumor suppressor in this malignancy. Subsequent genetic experiments showed that ablating Prdm16 along with Smad4 resulted in a shift from a well-differentiated and confined neoplasm to a highly aggressive and metastatic disease, which was associated with a striking deviation …

Selective Reprogramming Of Regulatory T Cells In Solid Tumors Can Strongly Enhance Or Inhibit Tumor Growth, Rami Alfar, John V Napoleon, Imrul Shahriar, Richard Finnell, Cole Walchle, Austin Johnson, Philip S Low

Faculty, Staff and Students Publications

Folate receptor delta (FRδ) has been used as a biomarker for regulatory T cells (Tregs), because its expression is limited to Tregs and ovum. Although FRδ is unable to bind folate, we have used molecular docking software to identify a folate congener that binds FRδ with high affinity and have exploited this FRδ-specific ligand to target attached drugs (imaging agents, immune activators, and immune suppressors) specifically to Tregs in murine tumor xenografts. Analysis of treated tumors demonstrates that targeting of a Toll-like receptor 7 agonist inhibits Treg expression of FOXP3, PD-1, CTLA4, and HELIOS, resulting in 40-80% reduction in tumor …

The Nr2f2-Hand2 Signaling Axis Regulates Progesterone Actions In The Uterus At Early Pregnancy, Yeongseok Oh, Elvis Quiroz, Tianyuan Wang, Yassmin Medina-Laver, Skylar Montague Redecke, Francisco Dominguez, John P Lydon, Francesco J Demayo, San-Pin Wu

Faculty, Staff and Students Publications

Endometrial function is dependent on a tight crosstalk between the epithelial and stromal cells of the endometrium. This communication is critical to ensure a fertile uterus and relies on progesterone and estrogen signaling to prepare a receptive uterus for embryo implantation in early pregnancy. One of the key mediators of this crosstalk is the orphan nuclear receptor NR2F2, which regulates uterine epithelial receptivity and stromal cell differentiation. In order to determine the molecular mechanism regulated by NR2F2, RNAseq analysis was conducted on the uterus of

Loss Of Ubiquitin-Specific Peptidase 18 Destabilizes 14-3-3Ζ Protein And Represses Lung Cancer Metastasis, Zibo Chen, Lin Zheng, Yulong Chen, Xiuxia Liu, Masanori Kawakami, Lisa Maria Mustachio, Jason Roszik, Katherine V Ferry-Galow, Ralph E Parchment, Xin Liu, Thorkell Andresson, Gerard Duncan, Jonathan M Kurie, Jaime Rodriguez-Canales, Xi Liu, Ethan Dmitrovsky

Faculty, Staff and Student Publications

Cancer metastasis is a major cause of cancer-related mortality. Strategies to reduce metastases are needed especially in lung cancer, the most common cause of cancer mortality. We previously reported increased ubiquitin-specific peptidase 18 (USP18) expression in lung and other cancers. Engineered reduction of USP18 expression repressed lung cancer growth and promoted apoptosis. This deubiquitinase (DUB) stabilized targeted proteins by removing the complex interferon-stimulated gene 15 (ISG15). This study explores if the loss of USP18 reduced lung cancer metastasis. USP18 knock-down in lung cancer cells was independently achieved using small hairpin RNAs (shRNAs) and small interfering RNAs (siRNAs). USP18 knock-down reduced …

Clinical Significance Of Glycolytic Metabolic Activity In Hepatocellular Carcinoma, Joann Jung, Sowon Park, Yeonwoo Jang, Sung-Hwan Lee, Yun Seong Jeong, Sun Young Yim, Ju-Seog Lee

Faculty, Staff and Student Publications

High metabolic activity is a hallmark of cancers, including hepatocellular carcinoma (HCC). However, the molecular features of HCC with high metabolic activity contributing to clinical outcomes and the therapeutic implications of these characteristics are poorly understood. We aimed to define the features of HCC with high metabolic activity and uncover its association with response to current therapies. By integrating gene expression data from mouse liver tissues and tumor tissues from HCC patients (n = 1038), we uncovered three metabolically distinct HCC subtypes that differ in clinical outcomes and underlying molecular biology. The high metabolic subtype is characterized by poor …

Anti-Cancer Mechanisms Of Action Of Therapeutic Alternating Electric Fields (Tumor Treating Fields [Ttfields]), Shadi Shams, Chirag B Patel

Faculty, Staff and Student Publications

Despite improved survival outcomes across many cancer types, the prognosis remains grim for certain solid organ cancers including glioblastoma and pancreatic cancer. Invariably in these cancers, the control achieved by time-limited interventions such as traditional surgical resection, radiation therapy, and chemotherapy is short-lived. A new form of anti-cancer therapy called therapeutic alternating electric fields (AEFs) or tumor treating fields (TTFields) has been shown, either by itself or in combination with chemotherapy, to have anti-cancer effects that translate to improved survival outcomes in patients. Although the pre-clinical and clinical data are promising, the mechanisms of TTFields are not fully elucidated. Many …

Spatial Heterogeneity Of Infiltrating T Cells In High-Grade Serous Ovarian Cancer Revealed By Multi-Omics Analysis, Bin Yang, Xiong Li, Wei Zhang, Junpeng Fan, Yong Zhou, Wenting Li, Jingjing Yin, Xiaohang Yang, Ensong Guo, Xi Li, Yu Fu, Si Liu, Dianxing Hu, Xu Qin, Yingyu Dou, Rourou Xiao, Funian Lu, Zizhuo Wang, Tianyu Qin, Wei Wang, Qinghua Zhang, Shuaicheng Li, Ding Ma, Gordon B Mills, Gang Chen, Chaoyang Sun

Faculty, Staff and Student Publications

Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, represent a favorable prognostic factor in high-grade serous ovarian cancer (HGSOC) and other tumor lineages. Here, we analyze the spatial heterogeneity of different TIL subtypes in HGSOC. We integrated RNA sequencing, whole-genome sequencing, bulk T cell receptor (TCR) sequencing, as well as single-cell RNA/TCR sequencing to investigate the characteristics and differential composition of TILs across different HGSOC sites. Two immune "cold" patterns in ovarian cancer are identified: (1) ovarian lesions with low infiltration of mainly dysfunctional T cells and immunosuppressive Treg cells and (2) omental lesions infiltrated with non-tumor-specific bystander cells. Exhausted CD8 T …

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.

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 …

Editorial: Epigenetics And Molecular Genetics Of Rare Tumors, Mauro Tognon, George A. Calin, Luis Del Valle

School of Medicine Faculty Publications

No abstract provided.

Triphenyl Phosphate Activates Estrogen Receptor Α/Nf-Κb/ Cyclin D1 Signaling To Stimulate Cell Cycle Progression In Human Ishikawa Endometrial Cancer Cells, Hyun Young Kwon, Seung Bin Park, Myoungseok Han, Jung-Woo Park, Yongmin Lee, Sang Jun Han, Youngmin Kwon, Yeon Jean Cho

Faculty, Staff and Students Publications

OBJECTIVE: Triphenyl phosphate (TPHP) is one of the most commonly used organophosphorus flame retardants that may accumulate in the environment. However, its effects on human reproductive organs have not been well studied. We aimed to investigate the in vitro effects of TPHP in human Ishikawa endometrial cancer cells to elucidate how TPHP exposure disrupts intracellular signaling and cell proliferation in reproductive tissues.

METHODS: Human Ishikawa endometrial cancer cells were exposed to TPHP.

RESULTS: Exposure to TPHP elevated the levels of estrogen receptor (ER) α and progesterone receptor-B and reduced ER β in human Ishikawa endometrial cancer cells. TPHP stimulated phosphoinositide …

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 …

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 …

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 …

Mab21l4 Deficiency Drives Squamous Cell Carcinoma Via Activation Of Ret, Ankit Srivastava, Cristina Tommasi, Dane Sessions, Angela Mah, Tomas Bencomo, Jasmine M Garcia, Tiffany Jiang, Michael Lee, Joseph Y Shen, Lek Wei Seow, Audrey Nguyen, Kimal Rajapakshe, Cristian Coarfa, Kenneth Y Tsai, Vanessa Lopez-Pajares, Carolyn S Lee

Faculty, Staff and Students Publications

UNLABELLED: Epithelial squamous cell carcinomas (SCC) most commonly originate in the skin, where they display disruptions in the normally tightly regulated homeostatic balance between keratinocyte proliferation and terminal differentiation. We performed a transcriptome-wide screen for genes of unknown function that possess inverse expression patterns in differentiating keratinocytes compared with cutaneous SCC (cSCC), leading to the identification of MAB21L4 (C2ORF54) as an enforcer of terminal differentiation that suppresses carcinogenesis. Loss of MAB21L4 in human cSCC organoids increased expression of RET to enable malignant progression. In addition to transcriptional upregulation of RET, deletion of MAB21L4 preempted recruitment of the CacyBP-Siah1 E3 ligase …

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. …

Cyclase-Associated Protein 1 (Cap1) In Cyclic Adenosine Monophosphate (Camp) And Protein Kinase C (Pkc) Signals To Regulate Cancer Cell Functions, Lokesh Kalki Mani Sai Akana

Student Theses and Dissertations

Cyclase-Associated Protein 1 (CAP1) is an actin-regulating protein that promotes actin dynamics and is also involved in cell adhesion and proliferation as well as implicated in human cancers. We previously found that phosphorylation at the Ser307/Ser309 tandem regulatory site on CAP1 is critical for CAP1 functions in breast and pancreatic cancer cells. We silenced CAP1 through RNAi in HCT116 and SW480 colon cancer cells as confirmed in Western blotting. We have found that depletion of CAP1 led to reduced FAK (Focal Adhesion Kinase) activity and matrix adhesion in SW480 cells, while it stimulated FAK activity and cell adhesion in HCT116 …

Early Growth Response 1 Transcription Factor Is Essential For The Pathogenic Properties Of Human Endometriotic Epithelial Cells, Vineet K Maurya, Maria M Szwarc, Rodrigo Fernandez-Valdivia, David M Lonard, Song Yong, Niraj Joshi, Asgerally T Fazleabas, John P Lydon

Faculty, Staff and Students Publications

Although a non-malignant gynecological disorder, endometriosis displays some pathogenic features of malignancy, such as cell proliferation, migration, invasion and adaptation to hypoxia. Current treatments of endometriosis include pharmacotherapy and/or surgery, which are of limited efficacy and often associated with adverse side effects. Therefore, to develop more effective therapies to treat this disease, a broader understanding of the underlying molecular mechanisms that underpin endometriosis needs to be attained. Using immortalized human endometriotic epithelial and stromal cell lines, we demonstrate that the early growth response 1 (EGR1) transcription factor is essential for cell proliferation, migration and invasion, which represent some of the …

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).

Hippo-Taz Signaling Is The Master Regulator Of The Onset Of Triple-Negative Basal-Like Breast Cancers, Hirotoshi Soyama, Miki Nishio, Junji Otani, Toshiko Sakuma, Shintaro Takao, Shigeo Hara, Takaaki Masuda, Koshi Mimori, Shinya Toyokuni, John P Lydon, Kazuwa Nakao, Hiroshi Nishina, Takumi Fukumoto, Tomohiko Maehama, Akira Suzuki

Faculty, Staff and Students Publications

A universal oncogenic driver of basal-like breast cancer (BLBC) has resisted identification. We show that continuous transcriptional coactivator with PDZ-binding motif (TAZ) activation in precancerous murine luminal cells generates luminal cancers that later become BLBCs. Subsequent TP53 alteration, a feature of invasive human BLBCs, accelerates tumor progression. Because BLBC development is inhibited by TAZ inactivation in vivo, our work provides a sound rationale for targeting Hippo-TAZ signaling as therapy for human BLBC. Our mouse model of BLBC represents a powerful tool for evaluating such drugs.

Triplet Therapy, Transplantation, And Maintenance Until Progression In Myeloma, Paul G Richardson, Susanna J Jacobus, Edie A Weller, Hani Hassoun, Sagar Lonial, Noopur S Raje, Eva Medvedova, Philip L Mccarthy, Edward N Libby, Peter M Voorhees, Robert Z Orlowski, Larry D Anderson, Jeffrey A Zonder, Carter P Milner, Cristina Gasparetto, Mounzer E Agha, Abdullah M Khan, David D Hurd, Krisstina Gowin, Rammurti T Kamble, Sundar Jagannath, Nitya Nathwani, Melissa Alsina, R Frank Cornell, Hamza Hashmi, Erica L Campagnaro, Astrid C Andreescu, Teresa Gentile, Michaela Liedtke, Kelly N Godby, Adam D Cohen, Thomas H Openshaw, Marcelo C Pasquini, Sergio A Giralt, Jonathan L Kaufman, Andrew J Yee, Emma Scott, Pallawi Torka, Amy Foley, Mariateresa Fulciniti, Kyle Hebert, Mehmet K Samur, Kelly Masone, Michelle E Maglio, Andrea A Zeytoonjian, Omar Nadeem, Robert L Schlossman, Jacob P Laubach, Claudia Paba-Prada, Irene M Ghobrial, Aurore Perrot, Philippe Moreau, Hervé Avet-Loiseau, Michel Attal, Kenneth C Anderson, Nikhil C Munshi, Determination Investigators

Faculty, Staff and Students Publications

BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown.

METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received …

Mir-181a Promotes Multiple Protumorigenic Functions By Targeting Tgfβr3, Vida Chitsazzadeh, Tran N Nguyen, Alvaro De Mingo Pulido, Bruna B Bittencourt, Lili Du, Charles H Adelmann, Ivannie Ortiz Rivera, Kimberly A Nguyen, Leah D Guerra, Andrew Davis, Marco Napoli, Wencai Ma, Richard Eric Davis, Kimal Rajapakshe, Cristian Coarfa, Elsa R Flores, Kenneth Y Tsai

Faculty, Staff and Students Publications

Cutaneous squamous cell carcinoma (cSCC) comprises 15‒20% of all skin cancers and has a well-defined progression sequence from precancerous actinic keratosis to invasive cSCC. To identify targets for chemoprevention, we previously reported a cross-species analysis to identify the transcriptional drivers of cSCC development and identified miR-181a as a potential oncomiR. We show that the upregulation of miR-181a promotes multiple protumorigenic properties by targeting an understudied component of TGFβ signaling, TGFβR3. miR-181a and TGFβR3 are upregulated and downregulated, respectively, in cSCC. miR-181a overexpression (OE) and TGFβR3 knockdown (KD) significantly suppresses UV-induced apoptosis in HaCaT cells and in primary normal human epidermal …

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 …