Mechanisms Underlying Dedifferentiation and Tumorigenesis

Faculty Information

Faculty Name: Myon-Hee Lee

Department: Medicine

Contact Information: leemy@ecu.edu; 252-744-3134

 

Research Description

Highlights of Research: 

Dedifferentiation is the reverse developmental process in which differentiated cells with specialized functions revert to a more undifferentiated and multipotent cells. This process is important for replacing a lost stem cell population and has been implicated in the formation of tumor-initiating cells (sometimes called cancer stem cells). Although dedifferentiation has been observed in tissue culture cells and in organisms, the mechanism of dedifferentiation is still poorly understood.

Our research group will investigate the mechanisms underlying dedifferentiation, and elucidate the relationship between dedifferentiation and tumorigenesis in molecular and cellular pathways. Specifically, we will address two fundamental molecular controls of dedifferentiation in vivo. First, how do differentiated cells either maintain or lose their identity? Second, which regulators normally inhibit dedifferentiation in determined germ cells? To address these questions, we have used the nematode Caenorhabditis elegans (C. elegans) germline as a model system. The C. elegans germline offers exceptional advantages for studying the regulation of germline stem cells (GSCs), differentiation, and cell fate reprogramming in vivo. We recently reported that C. elegans PUF-8 (a member of the PUF protein family) and LIP-1 (an MPK-1/ERK phosphatase) repress dedifferentiation by inhibiting MPK-1 (an ERK homolog) signaling in the C. elegans germline. Our preliminary studies have now identified several key regulators that normally inhibit the dedifferentiation of germ cells. Among them are conserved RNA regulators (GLD-1, GLD-2, CGH-1 and CAR-1), localized in germ granules (known as P granules in C. elegans), and B-type Cyclins. It hypothesizes that dedifferentiation of differentiated cells can be reduced to 3 simple mechanisms: MPK-1/ERK signaling, mRNA translational control, and Cyclin B activity. The significant directions of our proposal are three-fold:

o Identification of several germ granule-associated proteins (henceforth called germ granule proteins) that control differentiation/dedifferentiation decision. C. elegans germ granules share components with the P bodies and stress granules in mammals. LIN28, an RNA-binding protein, was previously identified as a dedifferentiation factor in human cells in conjunction with OCT4, SOX2, and NANOG. LIN-28 plays a role in regulating mRNA translation or stability, and appears to shuttle from the nucleus to P bodies. In addition, NANOS, a conserved germ granule protein, is also required for regeneration of the germline in planaria. Therefore, we suggest that germ granule proteins may have a conserved role in dedifferentiation and regenerative medicine.

o Identification of CYB-2.1 and CYB-2.2 (92% identical; henceforth called CYB-2) that are critical for the terminal differentiation (meiotic division) of spermatocytes into sperm. RNAi (RNA interference) of either cyb-2.1 or cyb-2.2 arrested germ cells in spermatocytes and led to the dedifferentiation of the arrested spermatocytes in puf-8 mutants. This is a new finding to show the role of cell cycle regulator in spermatogenesis and differentiation/dedifferentiation decision. This aim will address a novel mechanism of how cell cycle and developmental regulators are integrated within a tissue to control cellular events in vivo.

o Cancer relevance. A hallmark of tumor-initiating cells is the capacity of unlimited self-renewal, which is also a defining characteristic of normal stem cells. Moreover, tumor-initiating cells may arise from the dedifferentiation of more differentiated cell types and are believed to exist in multiple solid tumors. Therefore, better understanding of all the regulators and mechanisms involved in differentiation/dedifferentiation decision will lead us to novel and innovative approaches for the identification of therapeutic targets or the prevention of human cancers.

We therefore expect that student researcher discover a role for P-granule-associated regulators in dedifferentiation as well as publish his/her results to a peer reviewed journal.

 

Qualifications

Requirements: N/A

 

 

Time Commitment 

Time commitment per week: 15 hours per week

Start Date: Anytime

 

Compensation

Student may receive Independent Study course credit through this opportunity.

In addition, we will submit a research grant proposal for undergraduate study to NSF or other federal/private grant agencies. If the proposal is funded, Honors College Students’ stipend will be supported by the research grant. Currently, one student’s stipend in my lab is supported by Private grant.

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