The Mendell laboratory works at the leading-edge of RNA biology and cancer biology, investigating noncoding RNA functions, the roles of noncoding RNAs in tumorigenesis, and the application of RNA-based tools to elucidate noncoding RNA and tumor biology. We have made major contributions to our understanding of the roles of noncoding RNAs in cancer, with a particular focus on the microRNA (miRNA) pathway. Our early work in this area demonstrated that miRNAs function as critical components of key oncogenic and tumor suppressor networks, including the MYC, KRAS, and p53 pathways. My laboratory has been at the forefront of elucidating miRNA functions in vivo and translating these findings into novel therapeutic approaches, most notably through our demonstration that systemic delivery of miRNAs potently suppresses tumorigenesis in mouse cancer models without toxicity. We have also advanced our understanding of miRNA regulation, identifying examples of regulated miRNA biogenesis and decay. Looking ahead, this is a particularly important and exciting time for exploring the interface of RNA biology and tumor biology. After more than a decade of research into the roles of miRNAs in cancer, our understanding of how miRNAs contribute to tumorigenesis in vivo is still surprisingly limited. There is thus a great nee for the derivation and analysis of novel in vivo models of miRNA gain- and loss-of-function. We have also learned that perturbations of miRNA maturation, either through mutations in components of the miRNA biogenesis machinery or through aberrant activity of specific miRNA regulatory pathways, are a common feature of human malignancies. Nevertheless, precisely how miRNA maturation is regulated in cancer remains poorly understood. Beyond the miRNA pathway, we now know of the existence of thousands of long noncoding RNAs (lncRNAs) that participate in diverse cellular and developmental functions in mammals. Emerging data implicate an important role for lncRNAs in cancer, but we are at the earliest stages of understanding the underlying mechanisms. Finally, the emergence of powerful RNA-based tools for genome editing has provided unprecedented opportunities for functional analysis of noncoding RNAs in vivo. Based on these gaps in our knowledge and new research opportunities, the next phase of our research will focus on 1) the analysis of miRNA functions in normal physiology and cancer in vivo using novel gain- and loss-of-function mouse models; 2) investigation of the regulation of miRNA processing in normal development and tumorigenesis; 3) elucidation of lncRNA functions in normal physiology and cancer using cellular and animal models; and 4) application of CRISPR-based genomic editing to illuminate noncoding RNA functions in cells and animals and to discover and validate novel regulators of malignancy-associated phenotypes. My laboratory is uniquely positioned to synthesize these areas of research and thereby continue our track record of sustained productivity and leadership within the noncoding RNA and cancer biology communities.

Public Health Relevance

This project proposes to investigate the regulation and function of noncoding RNAs in cancer, a leading cause of death in the United States. It is now recognized that specific types of noncoding RNAs, such as microRNAs, play important roles in all aspects of human malignancy and therefore further understanding of how their levels are regulated and the pathways they control may reveal new therapeutic approaches for this disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA197311-06
Application #
9985031
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Fingerman, Ian M
Project Start
2015-08-12
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Kopp, Florian; Mendell, Joshua T (2018) Functional Classification and Experimental Dissection of Long Noncoding RNAs. Cell 172:393-407
Chen, Kenneth S; Stroup, Emily K; Budhipramono, Albert et al. (2018) Mutations in microRNA processing genes in Wilms tumors derepress the IGF2 regulator PLAG1. Genes Dev 32:996-1007
Quirin, Kayla A; Kwon, Jason J; Alioufi, Arafat et al. (2018) Safety and Efficacy of AAV Retrograde Pancreatic Ductal Gene Delivery in Normal and Pancreatic Cancer Mice. Mol Ther Methods Clin Dev 8:8-20
Heller, Kristin N; Mendell, Joshua T; Mendell, Jerry R et al. (2017) MicroRNA-29 overexpression by adeno-associated virus suppresses fibrosis and restores muscle function in combination with micro-dystrophin. JCI Insight 2:
Golden, Ryan J; Chen, Beibei; Li, Tuo et al. (2017) An Argonaute phosphorylation cycle promotes microRNA-mediated silencing. Nature 542:197-202
Lee, Sungyul; Kopp, Florian; Chang, Tsung-Cheng et al. (2016) Noncoding RNA NORAD Regulates Genomic Stability by Sequestering PUMILIO Proteins. Cell 164:69-80
Kent, Oliver A; Mendell, Joshua T; Rottapel, Robert (2016) Transcriptional Regulation of miR-31 by Oncogenic KRAS Mediates Metastatic Phenotypes by Repressing RASA1. Mol Cancer Res 14:267-77
Chang, Tsung-Cheng; Pertea, Mihaela; Lee, Sungyul et al. (2015) Genome-wide annotation of microRNA primary transcript structures reveals novel regulatory mechanisms. Genome Res 25:1401-9
Wu, Linwei; Nguyen, Liem H; Zhou, Kejin et al. (2015) Precise let-7 expression levels balance organ regeneration against tumor suppression. Elife 4:e09431