Jennifer Yu, MD, PhD
Staff
Center for Cancer Stem Cell Research
Location: Cleveland Clinic Main Campus
Research
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. Our laboratory has made seminal contributions in the understanding of the glioblastoma cellular hierarchy as it relates to different microenvironmental contexts. Glioma stem cells (GSCs) reside in different niches, including the perivascular and hypoxic niches. My laboratory has found that GSCs in different niches utilize distinct pathways to maintain stemness. We have discovered new mechanisms of regulation of two of the most important stem cell regulatory pathways, the Notch and Wnt pathways, in GSCs in these different niches (Cell Stem Cell, Cell Reports, Nature Communications). As a result, tailored approaches are needed to kill GSC populations in the different niches. This is an important concept with significant clinical ramifications. Ongoing projects aim to identify novel drivers of GSC progression and therapeutic resistance.
My patients have impressed upon me the urgent need for better treatments. My laboratory research, therefore, is geared toward having a direct impact in clinical care. To this end, we have launched two investigator-initiated clinical trials (IITs) based on our work. One clinical trial (NCT02970448) is based our work showing that hyperthermia not only sensitizes GSCs to radiation but also suppresses radiation-induced survival signaling (Cancer Research). Our clinical trial demonstrates the safety and efficacy of expediting chemoradiation after laser hyperthermia for patients with GBM to take advantage of the radiosensitization of GSCs, improved penetration of chemotherapy due to disruption of the blood brain barrier, and augmented anti-tumor immune response. This trial has the potential to change standard of care. Our studies and that of our colleagues in the field of cancer neuroscience highlight crosstalk between nerves and cancer cells. These studies led to our clinical trial investigating electrical activity at the interface of “normal brain” and tumor in patients with GBM. This trial tests the hypothesis that the extent and pattern of electrical activity can predict future sites of disease progression and therefore inform regions for supramarginal tumor resection and radiotherapy intensification (NCT05565118). This is the first clinical trial to combine deep electrode recordings at the brain-tumor interface along with site directed biopsies at sites of electrical recordings to define the quality and extent of electrical signaling on tumor progression and its mechanistic basis.
Biography
Dr. Jennifer Yu is a Staff in the Department of Radiation Oncology, Department of Cancer Biology, Center for Cancer Stem Cell Biology at the Cleveland Clinic, and co- Leader of the Developmental Therapeutics Program and co-Leader of the Cancer Stem Cell Working Group at the NCI-designated Case Comprehensive Cancer Center. She specializes in radiation oncology with a focus on brain tumors. She is the Founding Director of the Center for Hyperthermia at the Cleveland Clinic.
Education & Professional Highlights
Dr. Yu completed her MD and PhD degrees at Columbia University and radiation oncology residency at the University of California, San Francisco. She has served as President of the Society for Thermal Medicine, Radiation Oncology Representative of the Society for Neuro-Oncology, and serves on the American Brain Tumor Association Clinical Advisory Board. Dr. Yu was named a Top Oncologist by Ohio Magazine, a recipient of the Gita Gidwani Mid-Career Leadership Fellowship, Lerner Rising Star Award, Cleveland Clinic Excellence in Science Award, and is a member of the prestigious American Society for Clinical Investigation.
Research
Ongoing Research Directions
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 maintenance and cell state plasticity. GSCs share many properties with normal stem cells. We aim to understand mechanisms by which GSCs re-activate core developmental pathways, including the Semaphorin, Notch, Wnt, TGFbeta pathways, and cross-talk between these pathways. We also assess epigenetic regulation of cell state plasticity to inform therapeutic strategies of cellular differentiation for GBM.
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. 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-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 engineering colleagues to assess interactions and electrical activity between cancer cells, neurons, and immune cells.
4. 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.
5. 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.
6. 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.
Our Team
Selected Publications
Bharti Rashmi, Dey Goutam, Khan Debjit, Myers Alex, Huffman Olivia G, Saygin Caner, Braley Chad, Richards Elliott, Sangwan Naseer, Willard Belinda, Lathia Justin D, Fox Paul L, Lin Feng, Jha Babal Kant, Brown J Mark, Yu Jennifer S, Dwidar Mohammed, Joehlin-Price Amy, Vargas Roberto, Michener Chad M, Longworth Michelle S, Reizes Ofer. Cell surface CD55 traffics to the nucleus leading to cisplatin resistance and stemness by inducing PRC2 and H3K27 trimethylation on chromatin in ovarian cancer. Mol Cancer. 2024. 38853277.
Murphy Erin S, Yang Kailin, Suh John H, Yu Jennifer S, Stevens Glen, Angelov Lilyana, Barnett Gene H, Neyman Gennady, Mohammadi Alireza M, Chao Samuel T. Phase I trial of dose escalation for preoperative stereotactic radiosurgery for patients with large brain metastases. Neuro Oncol. 2024. 38656347.
Huang Haidong, Shah Hariti, Hao Jing, Lin Jianhong, Prayson Richard A, Xie Liangqi, Bao Shideng, Chakraborty Abhishek A, Jankowsky Eckhard, Zhao Jianjun, Yu Jennifer S. LncRNA LUCAT1 Promotes Glioblastoma Progression by Enhancing HIF1α Activity. Neuro Oncol. 2024. 38456228.
Tom Martin C, DiFilippo Frank P, Jones Stephen E, Suh John H, Obuchowski Nancy A, Smile Timothy D, Murphy Erin S, Yu Jennifer S, Barnett Gene H, Angelov Lilyana, Mohammadi Alireza M, Huang Steve S, Wu Guiyun, Johnson Scott, Peereboom David M, Stevens Glen H J, Ahluwalia Manmeet S, Chao Samuel T. F-fluciclovine PET/CT to distinguish radiation necrosis from tumor progression for brain metastases treated with radiosurgery: results of a prospective pilot study. J Neurooncol. 2023. 37341842.
Hao Jing, Han Xiangzi, Huang Haidong, Yu Xingjiang, Fang Jiankang, Zhao Jianjun, Prayson Richard A, Bao Shideng, Yu Jennifer S. Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma. Nat Commun. 2023. 37080989.
Gorenflo Maria P, Shen Alan, Murphy Erin S, Cullen Jennifer, Yu Jennifer S. Area-level socioeconomic status is positively correlated with glioblastoma incidence and prognosis in the United States. Front Oncol. 2023. 37007113.
Billena Cole, Lobbous Mina, Cordova Christine A, Peereboom David, Torres-Trejo Alejandro, Chan Timothy, Murphy Erin, Chao Samuel T, Suh John, Yu Jennifer S. The role of targeted therapy and immune therapy in the management of non-small cell lung cancer brain metastases. Front Oncol. 2023. 36910642.
. H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models. J Clin Invest. 2022. 36125896.
Lauko Adam, Volovetz Josephine, Turaga Soumya M, Bayik Defne, Silver Daniel J, Mitchell Kelly, Mulkearns-Hubert Erin E, Watson Dionysios C, Desai Kiran, Midha Manav, Hao Jing, Bao Shideng, Yu Jennifer S, Lathia Justin D. SerpinB3 drives cancer stem cell survival in glioblastoma. Cell Rep. 2022. 36103817.
Tewari Surabhi, Park Deborah Y J, Wei Wei, Chao Samuel T, Yu Jennifer S, Suh John H, Kilic Sarah, Peereboom David M, Stevens Glen H J, Lathia Justin D, Prayson Richard, Barnett Gene H, Angelov Lilyana, Mohammadi Alireza M, Murphy Erin S. Sex-Specific Differences in Low-Grade Glioma Presentation and Outcome. Int J Radiat Oncol Biol Phys. 2022. 35667529.
Park Deborah Y, Chen Yanwen, Tewari Surabhi, Yu Jennifer S, Chao Samuel T, Suh John H, Peereboom David M, Stevens Glen H J, Barnett Gene H, Angelov Lilyana, Mohammadi Alireza, Hogan Thomas, Kissel Courtney, Lapin Brittany, Schuermeyer Isabel, Naugle Richard, Murphy Erin S. Cognitive function after concurrent temozolomide-based chemoradiation therapy in low-grade gliomas. J Neurooncol. 2022. 35486307.
Park Deborah Y, Wei Wei, Tewari Surabhi, Yu Jennifer S, Chao Samuel T, Suh John H, Peereboom David, Stevens Glen H J, Barnett Gene H, Angelov Lilyana, Mohammadi Alireza M, Hogan Thomas, Kissel Courtney, Lapin Brittany, Schuermeyer Isabel, Naugle Richard, Murphy Erin S. Quality of life following concurrent temozolomide-based chemoradiation therapy or observation in low-grade glioma. J Neurooncol. 2022. 35064450.
Knackstedt Rebecca, Smile Timothy, Yu Jennifer, Gastman Brian R. Non-Operative Options for Loco-regional Melanoma. Clin Plast Surg. 2021. 34503723.
Hao Jing, Buck Matthias, Yu Jennifer S. Interactions between semaphorins and plexin-neuropilin receptor complexes in the membranes of live cells. J Biol Chem. 2021. 34270956.
Fang Xiaoguang, Huang Zhi, Zhai Kui, Huang Qian, Tao Weiwei, Almasan Alexandru, Yu Jennifer S, Li Xiaoxia, Stark George R, Bao Shideng. Inhibiting DNA-PK induces glioma stem cell differentiation and sensitizes glioblastoma to radiation in mice. Sci Transl Med. 2021. 34193614.
Yu Jennifer S. Re-evaluating Biopsy for Recurrent Glioblastoma: A Position Statement by the Christopher Davidson Forum Investigators. Neurosurgery. 2021. 33862619.
Huang Haidong, Yu Xingjiang, Han Xiangzi, Hao Jing, Zhao Jianjun, Bebek Gurkan, Bao Shideng, Prayson Richard A, Khalil Ahmad M, Jankowsky Eckhard, Yu Jennifer S. Piwil1 Regulates Glioma Stem Cell Maintenance and Glioblastoma Progression. Cell Rep. 2021. 33406417.
Hu Yi, Amorim Tania, Maqbool Mohsin, Li Chen, Fang Chuanfeng, Fang Hua, Yin Mei, Janocha Allison J, Mejia-Garcia Alex, Anwer Faiz, Khouri Jack, Qi Xin, Zheng Qing Y, Yu Jennifer S, LaFramboise Thomas, Herlitz Leal C, Lin Jianhong, Zhao Jianjun. Cisplatin-Mediated Upregulation of APE2 Binding to MYH9 Provokes Mitochondrial Fragmentation and Acute Kidney Injury. Cancer Res. 2021. 33288657.
Tao Weiwei, Zhang Aili, Zhai Kui, Huang Zhi, Huang Haidong, Zhou Wenchao, Huang Qian, Fang Xiaoguang, Sloan Andrew E, Ahluwalia Manmeet S, Lathia Justin D, Yu Jennifer S, Bao Shideng. SATB2 drives glioblastoma growth by recruiting CBP to promote FOXM1 expression in glioma stem cells. EMBO Mol Med. 2020. 33124191.
McCallum Grant A, Shiralkar Jay, Suciu Diana, Covarrubias Gil, Yu Jennifer S, Karathanasis Efstathios, Durand Dominique M. Chronic neural activity recorded within breast tumors. Sci Rep. 2020. 32908180.
Yu Jennifer S, Mohammadi Alireza M. Introduction to laser thermal therapy for brain disorders. Int J Hyperthermia. 2020. 32672120.
Zhang Aili, Tao Weiwei, Zhai Kui, Fang Xiaoguang, Huang Zhi, Yu Jennifer S, Sloan Andrew E, Bao Shideng. Protein sumoylation with SUMO1 promoted by Pin1 in glioma stem cells augments glioblastoma malignancy. Neuro Oncol. 2020. 32592588.
Tao Weiwei, Chu Chengwei, Zhou Wenchao, Huang Zhi, Zhai Kui, Fang Xiaoguang, Huang Qian, Zhang Aili, Yu Xingjiang, Huang Haidong, Sloan Andrew E, Yu Jennifer S, Li Xiaoxia, Stark George R, Bao Shideng. Dual Role of WISP1 in maintaining glioma stem cells and tumor-supportive macrophages in glioblastoma. Nat Commun. 2020. 32541784.
Dharmaiah Sharvari, Zeng Johnathan, Rao Vinay S, Zi Ouyang, Ma Tianjun, Yu Kevin, Bhatt Heeruk, Shah Chirag, Godley Andrew, Xia Ping, Yu Jennifer S. Clinical and dosimetric evaluation of recurrent breast cancer patients treated with hyperthermia and radiation. Int J Hyperthermia. 2019. 31544546.
Tom Martin C, Park Deborah Y J, Yang Kailin, Wei Wei, Jia Xuefei, Varra Vamsi, Yu Jennifer S, Chao Samuel T, Balagamwala Ehsan H, Suh John H, Barnett Gene H, Prayson Richard A, Stevens Glen H J, Peereboom David M, Ahluwalia Manmeet S, Murphy Erin S. Malignant Transformation of Molecularly Classified Adult Low-Grade Glioma. Int J Radiat Oncol Biol Phys. 2019. 31461674.
Careers
Research News
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.