Center for Cancer Stem Cell Research
Location: Cleveland Clinic Main Campus
The mission of the Yu 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 and physicians.
Brain tumors fall into two categories, primary brain tumors, which originate in the brain, and brain metastases. Our major area of research is in glioblastoma, the most common primary malignant brain tumor. Glioblastoma is fatal despite multimodality therapy.
Dr. Yu is Staff in the Department of Cancer Biology and Department of Radiation Oncology, Center for Cancer Stem Cell Research. She is an Associate Professor of Molecular Medicine. She is a Program Leader of the Developmental Therapeutics Program at the Case Comprehensive Cancer Center, and co-Leader of the Cancer Stem Cell Working Group. Dr. Yu serves as President of the Society of Thermal Medicine, and Radiation Oncology Representative in the Society for Neuro-Oncology. She was named Top Doctor in Ohio Magazine and isan elected member of the prestigious American Society for Clinical Investigation.
Glioma stem cells (GSCs) are a subpopulation of cells that contribute to tumor progression and therapeutic resistance. GSCs have a high capacity for self-renewal, survival under hypoxic conditions, resistance to radiation and chemotherapy, and high invasive potential. GSCs reside in specialized niches that facilitate cell-cell and cell-microenvironmental conditions that maintain stemness and resistance to treatments.
Our lab is focused on delineating the molecular mechanisms underlying stem cell maintenance and therapeutic resistance of GSCs in different niches. Our long long-term goal is to uncover therapeutic vulnerabilities and target these pathways in clinic. We employ a number of approaches including multi-omic approaches, ribosome profiling, molecular biology, mouse modeling and human tissue analyses. Major areas of studies include the following:
1. GSC co-option of core developmental pathways. GSCs share many properties with normal stem cells. We aim to understand mechanisms by which GSCs re-activate developmental pathways, including the Semaphorin, Notch, Wnt, TGFbeta pathways, and cross-talk between these pathways.
2. GSC adaptations to hypoxia. GSCs frequently reside in a hypoxic niche. These GSCs are particularly resistant to treatment since clinically relevant radiation is dependent on oxygen, and chemotherapy is unable to be delivered to these areas. The hypoxia inducible factors (HIFs) integrate many cellular responses to hypoxia. We aim to understand HIF- dependent and independent mechanisms that contribute to GSC survival and therapeutic resistance. Current efforts include assessing an important yet poorly understood level of regulation: translation of genes involved in the hypoxic stress response. We are also investigating the role of hypoxia-regulated proteins and non-coding RNAs in GSC response to hypoxia.
3. Role of non-coding RNAs in GSC maintenance. Non-coding RNAs are increasingly recognized for their role in oncogenesis. These RNAs include small RNAs, circular RNAs and long non coding RNAs (lncRNAs). We aim to understand how these non-coding RNAs contribute to GSC maintenance.
4. Neural regulation of cancers. Many cancers including glioblastoma and breast cancer invade along axon tracks, and perineural invasion is a negative prognostic marker in numerous cancers. We identified the secreted axonal guidance cue Sema3C and its receptor complex NRP1-PlxnA2-PlxnD1 as an important pathway that is selectively used by glioma stem cells to promote their own cell survival and invasion. This pathway facilitates short range communication amongst glioma stem cells to maintain the GSC population and drive their invasion and resistance to radiation. In multi-disciplinary work, we also recorded for the first time direct electrical activity within breast cancers that is thought to promote breast cancer metastasis. We collaborate with our surgical and electrical engineering colleagues to assess interactions and electrical activity between cancer cells and neurons.
5. Effects of the microbiome in cancer progression. The microbiome is increasingly recognized for its role in cancer initiation and modulating responses to chemotherapy and immunotherapy. Current efforts focus on illuminating the role of the microbiome on radiation response in patients with glioblastoma.
6. Radiosensitization strategies. GSCs are highly resistant 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.
7. 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.
Huang H, Yu X, Han X, Hao J, Zhao J, Bebek G, Bao S, Prayson RA, Khalil AM, Jankowsky E, Yu JS*. Piwil1 Regulates Glioma Stem Cell Maintenance and Glioblastoma Progression. Cell Reports. 2021 Jan 5; 34(1):108522
Hu Y, Yang C, Amorim T, Maqbool M, Lin J, Li C, Fang X, Xue L, Kwart A, Fang H, Yin M, Janocha A, Tsuchimoto D, Nakabeppu Y, Jiang X, Mejia-Garcia A, Anwer F, Khouri J, Qi X, Zhang Q, Yu JS, Yan S, LaFramboise T, Anderson K, Herlitz L, Mushi K, Lin J, Zhao J. Cisplatin-mediated Upregulation of Apurinic/Apyrimidinic Endonuclease 2 (APE2) Binding to Myosin Heavy-chain 9 (MYH9) Provokes Mitochondrial Fragmentation and Acute Kidney Injury. Cancer Research. 2020 Dec 7
Tao W, Zhang A, Zhai K, Huang Z, Huang H, Zhou W, Huang Q, Fan X, Prager BC, Wang X, Wu Q, Sloan AE, Ahluwalia MS, Lathia JD, Yu JS. Rich JN, Bao S. SATB2 Drives Glioblastoma Growth by Recruiting CBP to Promote FOXM1 Expression in Glioma Stem Cells. EMBO Molecular Medicine. 2020 Oct 30:e12291
Zhang A, Tao W, Zhai K, Fang X, Huang Z, Yu JS, Sloan AE, Rich JN, Bao S, Protein Sumoylation with SUMO1 Promoted by PIN1 in Glioma Stem Cells Augments Glioblastoma Malignancy. Neuro-Oncology. 2020 Jun27:noaa150.
Yu JS*, Mohammadi AM, Introduction to Laser Thermal Therapy for Brain Disorders. International Journal of Hyperthermia. 2020; 37(2):1-2
McCallum G, Shiralkar J, Suciu D, Covarrubias G, Yu JS, Karathanasis E, Durand D, Chronic neural activity recorded within breast tumors. Scientific Reports. 2020; 10(1):14824
Tao W, Chu C, Zhou W, Huang Z, Zhai K, Fang X, Huang Q, Zhang A, Wang Z, Yu X, Huang H, Wu Q, Sloan A, Yu JS, Li X, Stark G, Rich J, Bao S, Dual Role of WISP1 in Maintaining Glioma Stem Cells and Tumor-supportive Macrophages in Glioblastoma. Nature Communications. 2020; 11(1):3015
Dharmaiah S, Zeng J, Rao VS, Zi O, Ma T, Yu K, Shah C, Bhatt H, Godley A, Xia P, Yu JS*, Clinical and dosimetric evaluation of recurrent breast cancer patients treated with hyperthermia and radiation. International Journal of Hyperthermia. 2019; 36(1):986-992
Tom M, Park DY, Yang K, Leyrer CM, Wei W, Jia X, Varra V, Yu JS, Chao ST, Balagamwala EH, Suh JH, Vogelbaum MA, Barnett GH, Prayson RA, Stevens GHJ, Peereboom DM, Ahluwalia MS, Murphy E, Malignant Transformation of Molecularly Classified Low Grade Glioma. International Journal of Radiation Oncology, Biology, and Physics 2019 Aug 25
Tom M, Varra V, Leyrer CM, Park DY, Chao ST, Yu JS, Suh JH, Reddy CA, Balagamwala EH, Broughman JR, Kotagal KA, Vogelbaum MA, Barnett GH, Ahluwalia MS, Peereboom DM, Prayson RA, Stevens GHJ, Murphy E, Risk Factors for Progression Among Low-Grade Gliomas Following Gross Total Resection and Initial Observation in the Molecular Era. International Journal of Radiation Oncology, Biology, and Physics 2019;104(5):1099-1105.
Abu-Gheida I, Chao S, Murphy E, Suh J, Stevens GH, Mohammadi A, McNamara M, Yu JS*, Targeted Therapy After Brain Radiotherapy for BRAF-Mutated Melanoma with Extensive Ependymal Disease With Prolonged Survival: Case Report and Review of the Literature. Frontiers in Oncology 2019 (9):168.
Hao J, Magnelli A, Godley AR, Yu JS*, Use of a Linear Accelerator for Conducting in vitro Radiobiology Experiments. JoVE, 2019 (147)
Juloori A, Miller H, Parsai S, Kotecha R, Ahluwalia M, Mohammadi A, Murphy E, Suh J, Barnett G, Yu JS, Vogelbaum M, Rini B, Garcia J, Stevens G, Angelov L, Chao S. Overall Survival and the Response to Radiation and Targeted Therapies Among Patients with Renal Cell Carcinoma Brain Metastases. Journal of Neurosurgery 2019 Jan 18:1-19.
Sittenfeld SMC, Suh J, Murphy ES, Yu JS, Chao ST, Contemporary Management of 1-4 Brain Metastases. Frontiers in Oncology 2018 Sept 24;8:385.
Hao J, Godley A, Han Z, Magnelli A, Yu JS*. The Effects of Extra High Dose Rate Irradiation on Glioma Stem-like Cells. PLOS One 2018 (Aug):1-14.
Pfannensteil L, McNeilly C, Xiang C, Kang K, Diaz-Montero C, Yu JS*, Gastman B. Combination PD-1 Blockade and Irradiation of Brain Metastasis Induces an Effective Abscopal Effect in Melanoma. OncoImmunology 2019; 8(1)e1507669
Rogacki K, Chao ST, Yu JS, Godley A, Balamwala E, Suh JS, Murphy ES. Review of Pulsed Reduced Dose Rate Re-irradiation for Recurrent Tumors. Journal of Cancer Clinical Trials 2018, 3(2):1-6.
Shi Y, Guryanova OA, Zhou W, Liu C, Huang Z, Fang X, Wang X, Chen C, Qu Q, He Z, Wang W, Zhang W, Jiang T, Liu Q, Chen Y, Wang W, Wu J, Kim L, Gimple RC, Feng H, Kung HF, Yu JS, Rich JN, Ping Y, Bian XW, Bao S. Ibrutinib Inactivates BMX-STAT3 in Glioma Stem Cells to Impair Malignant Growth and Radioresistance. Science Translational Medicine 2018; 10(443):1-13.
Hao J, Yu JS*. Semaphorin 3C and Its Receptors in Cancer and Cancer Stem-like Cells. Biomedicines 2018, 6(2):42.
Ouyang Z, Xia P, Vassil N, Yu KJ, Yu JS. Concomitant Hyperthermia and Intensity-modulated Radiation Therapy for a Large-field Chest Wall Re-irradiation. Applied Radiation Oncology 2018 Mar; 58-63.
Murphy ES, Leyrer MC, Ahluwalia M, Peereboom D, Stevens G, Barnett G, Vogelbaum M, Chao ST, Yu JS, Suh JH. Risk Factors for Malignant Transformation of Low Grade Glioma. International Journal of Radiation Oncology, Biology, and Physics 2018; 100(4):965-971.
Man J, Yu X, Huang H, Zhou W, Xiang C, Miele L, Liu Z, Bebek G, Bao S, Yu JS. Hypoxic Induction of Vasorin Regulates Notch1 Turnover to Maintain Glioma Stem-Like Cells. Cell Stem Cell 2018, 22:104-118.
Commentaries on this article:
-Recommended article of high significance by Faculty of 1000 (F1000Prime Faculty).
-The STAT3 and hypoxia pathways converge on Vasorin to promote stemness and glioblastoma tumorigenesis through Notch1 stabilization. Fan M, Pfeffer LM. Stem Cell Investigation. 2018; 5:35
-Picture of glioma stem cells has become a Notch brighter. Parajuli P, Mittal S. Stem Cell Investigation. 2018; 5:42
Zhou W, Chen C, Shi Y, Wu Q, Gimple RC, Fang X, Huang Z, Zhai K, Ke SQ, Ping YF, Feng H, Rich JN, Yu JS, Bao S, Bian XW. Targeting Glioma Stem-Cell Derived Pericytes Disrupts the Blood-Tumor Barrier to Improve Drug Delivery and Chemotherapeutic Efficacy. Cell Stem Cell 2017, 21:591-603.
Huang H, Yu X, Mohammadi AM, Karanthanasis E, Godley A, YuJS. It’s Getting Hot in Here: Targeting Cancer Stem-like Cells with Hyperthermia. Journal of Stem Cell and Transplantation Biology 2017, 2: 1-8.
Sharma M, Jia X, Ahluwalia M, Barnett GH, Vogelbaum MA, Chao ST, Suh JH, Murphy ES, Yu JS, Angelov L, Mohammadi AM. First Follow-up Radiographic Response is One of the Predictors of Local Tumor Progression and Radiation Necrosis After Stereotactic Radiosurgery for Brain Metastases. Cancer Medicine 2017 Sep; 6(9):2076-2086.
Murphy ES, Rogacki K, Godley A, Qi P, Reddy C, Ahluwalia M, Peereboom D, Stevens G, Yu JS, Suh JH, Chao ST. Intensity Modulated Radiation Therapy with Pulsed Reduced Dose Rate as a Re-irradiation Strategy for Recurrent Central Nervous System Tumors: An Institutional Series and Literature Review. Practical Radiation Oncology 2017 Nov-Dec;7(6):e391-e399.
Sharma M, Jia X, Ahluwalia M, Barnett GH, Vogelbaum MA, Chao ST, Suh JH, Murphy ES, Yu JS, Angelov L, Mohammadi AM. Cumulative Intracranial Tumor Volume and Number of Brain Metastases as Predictors of Developing New Lesions After Stereotactic Radiosurgery for Brain Metastasis. World Neurosurgery 2017 Oct; 106:666-675.
Kotecha R, Miller JA, Venur VA, Mohammadi AM, Chao ST, Suh JH, Barnett GH, Murphy ES, Funchain P, Yu JS, Vogelbaum MA, Angelov L, Ahluwalia MS. Melanoma Brain Metastasis: The Impact of Stereotactic Radiosurgery, BRAF Mutational Status, and Targeted/Immune-Based Therapies on Treatment Outcome. Journal of Neurosurgery 2017 Aug 11:1-10.
Bennett EE, Angelov A, Vogelbaum MA, Barnett GH, Chao ST, Murphy ES, Yu JS, Suh JH, Jia XJ, Glen HJ, Ahluwalia MS, Mohammadi, The Prognostic Role of Tumor Volume in the Outcome of Patients with Single Brain Metastasis After Stereotactic Radiosurgery. World Neurosurgery, 2017 Aug;104:229-238.
Mohammadi A, Schroeder J, Angelov L, Chao ST, Murphy E, Yu JS, Neyman G, Jia X, Suh J, Barnett G, Vogelbaum M, Impact of radiosurgery prescription dose on the local control of small (2 cm or less) brain metastases. Journal of Neurosurgery 2017, 126(3):735-743, PMID 27231978.
Miller JA, Bennett EE, Xiao R, Kotecha R, Chao ST, Vogelbaum MA, Barnett GH, Angelov L, Murphy ES, Yu JS, Ahluwalia MS, Suh JH, Mohammadi AM. Association between Radiation Necrosis and Tumor Biology following Stereotactic Radiosurgery for Brain Metastasis. International Journal of Radiation Oncology, Biology, and Physics 2016, 96:1060-1069.
Adams CS#, Yu JS#, Mao JH, Jen KY, Costes S, Wade M, Shoemake J, Aina OH, Del Rosario R, Thuy-Menchavez P, Cardiff R, Wahl GM, Balmain A, The Trp53 Delta Proline Mouse Exhibits Increased Genome Instability and Susceptibility to Radiation-Induced But Not Spontaneous Tumor Development. Molecular Carcinogenesis 2016, 55(9):1387-1396. PMID: 26310697, PMCID PMC4891300. #co-first author
Amoush A, Murray E, Yu JS, Xia P, Impact of Intra-Fraction Motion for the Treatment of Breast Cancer With Supraclavicular Lymph Nodes Using Single-Isocenter 4-Field Hybrid IMRT Plans versus Two-Isocenter Conventional Plans. Journal of Applied Clinical Medical Physics 2015, 16:31-39.
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.
Murphy ES, Xie H, Merchant TE, Yu JS, Chao S, Suh J, Review of Cranial Radiotherapy-Induced Vasculopathy. Journal of Neuro-oncology 2015, May 122(3): 421-429.
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.
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.
Marta GN, Murphy E, Chao S, Yu JS, Suh JH, The incidence of second brain tumors related to cranial irradiation. Expert Review of Anticancer Therapy 2014: 295-304.
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.
Zhuang T, Huang L, Qi P, Yu JS, Radiation therapy: Clinical application of volumetric modulated arc therapy. Applied Radiation Oncology 2013, 6.
Drs. Yu and Zhao will study the role of a long non-coding RNA called Lucat1 in glioma stem cells in the search for new therapeutics to help treat glioblastoma and overcome treatment resistance.