Stem Cell Biology and Regenerative Medicine
Jennifer Yu, M.D., Ph.D.
Lerner Research Institute
9500 Euclid Avenue
Cleveland, Ohio 44195
Phone: (216) 444-0852
Fax: (216) 636-5454
The mission of our lab is to improve therapy for patients with brain tumors by elucidating the molecular mechanisms driving cancer initiation and progression, and in doing so, promote rigorous science and train the next generation of scientists. We aim to expedite the translation of experimental therapeutics to clinical trials.
Brain tumors fall into two categories, primary brain tumors, which originate in the brain, and secondary brain tumors that metastasize to the brain. Our major area of research is in glioblastoma, the most common primary brain tumor. Glioblastoma is fatal despite multimodality therapy. Glioma stem cells (GSCs) are a subpopulation of cells that contribute to tumor progression. Glioma stem cells have a high capacity for self-renewal, survival under hypoxic conditions, resistance to radiation, and high invasive potential. Our lab is focused on understanding the mechanisms underlying these key GSC tumorigenic properties with a long-term goal of uncovering potential therapeutic targets.
1. GSC co-option of core developmental pathways, including the Semaphorin, Notch and Wnt pathways. We have identified that GSCs preferentially re-activate the Semaphorin-Neuropilin-Plexin axonal guidance program. GSCs secrete Sema3C and engage PlexinA2/PlexinD1 receptors to regulate GSC survival and invasion. We aim to illuminate mechanisms by which Sema3C contributes to tumor progression. We also aim to understand how the Notch and Wnt core stem cell programs are regulated by GSCs.
2. GSC adaptations to hypoxic conditions. GSCs frequently reside in the hypoxic niche. The hypoxia inducible factors (HIFs) integrate cellular responses to hypoxia. We aim to understand the repertoire of HIF-target genes that contribute to GSC survival and expansion.
3. GSC resistance to radiation due to upregulation of pro-survival signaling and enhanced DNA damage repair capacity. We are interested in improving the radiosensitivity of GSCs with thermal therapy, modifications in radiation delivery and radiosensitizing drugs.
4. Maintenance of GSCs by non-coding RNAs. Non-coding RNAs are increasingly recognized for their role in oncogenesis. These RNAs include small RNAs and lncRNAs. We aim to understanding how these non-coding RNAs contribute to GSC maintenance.
Brain metastases are the most common type of brain tumors, and it is estimated that about 1/3 of cancer patients will develop brain metastases. We aim to understand how brain metastases adapt to their environment and how we can target them better.
Man J, Shoemake S, Zhou W, Fang X, Wu Q, Rizzo A, Prayson R, Bao S, Rich JN, Yu JS*, Sema3C Promotes The Survival and Tumorigenicity of Glioma Stem Cells Through Rac1 Activation. Cell Reports 2014, 9(5):1812-26.
Man J, Shoemake S, Ma R. Rizzo A, Godley AR, Wu Q, Mohammadi A, Bao S, Rich JN, Yu JS*, Hyperthermia sensitizes glioma stem-like cells to radiation by inhibiting AKT signaling. Cancer Research 2015, 75(8):1960-9. PMID:25712125, PMCID: PMC4401644.
Fang X, Huang Z, zhou W, Wu Q, Sloan AE, Ouyang G, McLendon R, Yu JS, Rich JN, Bao S. The Transcription Factor ZFX Is Required for Maintaining the Tumorigenic Potential of Glioblastoma Stem Cells. Stem Cells 2014, 32(8): 2033-47.
Liu J, Lubelski D, Schonberg D, Wu Q, Hale J, Flavahan W, Man J, Hjelmeland A, Yu JS, Lathia J, Mulkearns-Hubert E, Rich JN, Phage Display Discovery of Novel Molecular Targets in Glioblastoma Initiating Cells. Cell Death and Differentiation 2014, 21(8):1325-39.
Hopkins BD, Fine B, Steinbach N, Dendy M, Rapp Z, Shaw J, Pappas K, Yu JS, Hodakoski C, Mense S, Klein J, Pegno S, Sulis M, Goldstein H, Amendolara B, Lei L, Maurer M, Bruce J, Canoll P, Hibshoosh H, Parsons RE, PTEN-Long, a secreted from of PTEN that enters cells to alter signaling and survival. Science 2013, 341(6144):399-402.
Rivera M, Sukhdeo K, Yu JS*, Ionizing radiation in glioblastoma initiating cells. Frontiers in Oncology 2013, 3:74.
Wong CE, Yu JS, Quigley DA, To MD, Jen KY, Del Rosario R, Balmain A, Inflammation and H-ras Signaling control epithelial-mesenchymal transition during skin tumor progression. Genes and Development 2013, 27:670-682.