Mechanisms of Oncogenesis

Mission

The mission of the Mechanisms of Oncogenesis (MOO) program at the University of Florida Health Cancer Institute is to understand how normal cells undergo complex changes leading to cancer.

The scientific objectives of the MOO program are to elucidate the deregulated genetic and epigenetic events that drive tumor initiation and progression and develop new cancer targeting strategies.

The research aims focus on identifying and characterizing genetic and epigenetic alterations, elucidating the role of noncoding RNAs in cancer, studying oncogenic mechanisms of DNA tumor viruses, and translating MOO discovery to novel therapeutic approaches.

Aims

The objectives of the MOO program are to identify and understand cellular pathways deregulated during neoplastic transformation and progression, decipher how these changes promote cancer phenotypes, and develop methodologies to target cancer-specific events. MOO members are studying the priority cancers in our CA as identified by COE using innovative in vitro and in vivo models. Members also established a strong program to study how human DNA tumor viruses deregulate epigenetic control and noncoding RNAs to drive tumorigenesis. The aims of the MOO program are:

• Aim 1. Elucidate the Role of Genetic and Epigenetic Alterations in Cancer.

Examples range from discovering the critical mechanisms underlying the oncogenes (EML4-ALK fusion, CRTC1-MAML2 fusion), tumor suppressor genes (LKB1, p16), oncohistones (H2B mutations), chromatin regulators (NSD2, DNMTs), and RNA modifying regulators (ALKBH5, YTHDC1) to validate therapeutic targets in solid and hematologic malignancies. Moreover, MOO members study DNA tumor viruses (KSHV, EBV) and have established viral oncogenesis models that led to the discovery of novel mechanisms on host-viral interactions affecting immunity and epigenetics. 

• Aim 2. Define the Role of Regulatory microRNAs and long noncoding RNAs in Oncogenesis.

MOO members are studying how aberrantly expressed ncRNAs drive oncogenesis. Examples range from basic discovery of novel miRNA maturation pathways and control of miRNAs/mRNA interactions to the discovery of human lncRNA in lung cancer with the potential for therapeutic and biomarker development. Novel ribonomics methods allow rigorous identification of miRNA targetomes of EBV and KSHV-associated tumors, as well as melanoma, and breast and colorectal cancers. These discoveries are poised to inform the development of RNA-based therapeutics. MOO members investigating RNA cancer biology also study virology and epigenetics and engage in productive collaborations leading to joint publications and MPI grants. 

• Aim 3. Translate MOO Discoveries into Novel Therapeutic Approaches.

MOO investigators discover and validate cancer drivers that represent potential therapeutic targets for precision medicine approaches. Examples include efforts to translate MOO findings on the susceptibilities of tumors harboring mutations of epigenetic regulators such as NSD2, KDM6A, DNMT3A. MOO research validated RNA modifying enzymes as molecular targets and showed how to target the BCL-XL anti-apoptotic protein with PROTACs in a spectrum of tumors. Translation of MOO discoveries is facilitated by collaboration among members across all 3 programs. Candidates for clinical development are evaluated in close collaboration between the investigator and the ADs for Basic Sciences, Translation and Innovation, and Clinical Research, and further advanced in the monthly IIT Think Tank. Trials based on MOO discoveries are performed collaboratively by clinical researchers, with all necessary infrastructure provided by the CRO. 

Program Co-leaders

Department: Molecular Genetics & Microbiology

Lizi Wu

Professor

Phone: (352) 273-8205

Email: lzwu@ufl.edu

Department: MD-PATHOLOGY-GENERAL

Weizhou Zhang

Professor, Vice Chair of Research

Email: zhangw@ufl.edu

Program Members

To request an update, please email ResearchDevelopment@cancer.ufl.edu.