Yun Lab

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About Our Lab

Research Projects

 
The Yun lab focuses on elucidating mechanisms that regulate therapy resistance and tumor recurrence in brain cancer with a goal of develop new therapies for glioblastoma and medulloblastoma patients. Our observations over the years and new knowledge in the field indicate that cell:cell communication and tumor microenvironment play major roles in modulating cancer stem cell maintenance, immune evasion, and therapy response. To identify cell-intrinsic and -extrinsic factors that control cancer stem cell proliferation, survival and differentiation, we develop and utilize genetically engineered mouse models, patient derived xenograft (PDX) models, primary tumorsphere cultures, and organotypic tumor slice cultures.
 
Areas of expertise:
  1. Cancer stem cells
  2. Glioblastoma
  3. Brain cancer
  4. Medulloblastoma
  5. Targeted therapy
  6. Diagnostic device
  7. Signaling pathways

 

Research Projects

Our analyses of brain cancer stem cell regulators have led us to expand our studies into tumor immunology and single cell genomics. Therefore, a major area of current research is elucidating the interplay between brain cancer stem cells and the tumor immune microenvironment. Towards this goal, we have sequenced over 250,000 cancer and immune cells from human and mouse gliomas and defined molecular phenotypes of glioma associated myeloid cells and deciphered cell:cell communication among different cell types within the local microenvironment. In addition, to translate our findings, we are developing a new small molecule inhibitors and therapeutic antibodies against dual regulators of cancer stem cells and immune suppression.


Targeting brain cancer stem cells
 
The discovery of stem cell-like cancer cells (cancer stem cells: CSCs) in human tumors opened the possibility for a new generation of anti-cancer therapies that target this critical population of cancer cells. CSCs are a subpopulation of cancer cells that are endowed with the defining characteristics of stem cells (self-renewal and multipotentiality) and the ability to initiate a tumor when transplanted. In theory, a single cancer stem cell can re-initiate tumor formation or form a metastatic tumor. Accumulating evidence indicates that CSCs are more resistant to chemo- and radiation-therapies compared to non-stem cancer cells from the same tumor, suggesting that targeting CSCs is necessary for improving long-term outcomes for cancer patients.

 

In an earlier study, we identified 45 genes that show differential expression patterns in glioma stem cells, compared to normal neural stem cells and non-stem glioma cells. Many of these genes are independent prognostic indicators of glioma patient survival and are expressed in a subset of cells in huma GBM tissues. We performed in depth analysis of one of these genes, S100A4, and validated that it is a novel marker and a regulator of glioma stem cells. We also showed that it is a master regulator of EMT and mesenchymal transition as it regulates expression of key EMT transcriptional regulators, such as SNAIL2 and ZEB1. Our findings suggest that inhibition S100A4 may simultaneously block glioma stem cell self-renewal/survival and mesenchymal transition in GBMs.

 

We are currently analyzing its mechanisms of action in promoting glioma stem cell survival and self-renewal and investigating its role in the crosstalk between glioma stem cell and tumor vasculature. In addition, we are developing inhibitors to block its function as potential new therapies for treating GBMs and other solid tumor. 

Multi-omics analysis of brain cancer,  integrating data from Single cell RNA sequencing, chip-seq, pathway analysis and patient survival data


Targeting regulators of immune suppression in brain cancer
 
One of the confounding factors for developing therapies that target CSCs is the heterogeneity of CSCs even within the same clinical tumor type. We discovered that a major contributor to CSC heterogeneity in the Ptch+/- model of medulloblastoma is the cell of origin. Using the CSC culture phenotype as an initial identifier of CSC subtypes, we identified three distinct tumor subtypes in the Ptch+/- model. These subtypes are histologically indistinguishable but molecularly distinct at the bulk tumor level and at the CSC level. We showed through cell type specific activation of the SHH pathway in vivo that transformation of neural stem cell and neural progenitor cells generate CSCs that are molecularly and cellularly distinct, particularly in their sensitivity to SHH inhibitors. Our work showed that CSC retain epigenetic memories of their cells of origin and that mitogenic pathways that drive CSC proliferation are the same as those driving its cell of origin.

 

We are currently testing multiple implications for understanding therapy resistance stemming from this study. First, this study demonstrated a novel mechanism of de novo therapy resistance to targeted therapy that does not require acquisition of new mutations but depends on the resident CSC phenotype. Second, it suggests that we may be able to predict a priori the types of mutations that will occur in therapy-resistant tumors: tumors in which CSCs depend on SHH signaling will necessarily acquire new mutations in the SHH pathway while tumors in which CSCs depend on other mitogenic pathways will not necessarily mutate within the SHH pathway. We are currently testing this hypothesis.


Elucidating cell: cell communication among different cell types in the brain tumor microenvironment
  
 
Single cell RNA sequencing from control and mutant medulloblastoma reveals differential cell: cell communication among various cell types in the tumor

Yap1 function in brain development and tumorigenesis
Developmental signaling pathways, such as the SHH, Notch, Wnt, and Hippo, are critical for stem cell regulation and cancer. We showed that Notch1 promotes NSC self-renewal in vivo in part by directly regulating the expression levels of limiting transcription factors in each of these pathways, including YAP1.  YAP1 is a transcription effector of the Hippo pathway and is elevated in many human cancers, including brain cancer.  We showed that YAP1 expression is sufficient to bypass the need for Notch pathway activation in NSC self-renewal in vitro.  Our analysis of Yap1-/- brain indicates that YAP is also required for normal brain development.  Currently, we are currently testing its role in brain tumor initiation and progression.  Furthermore, we are studying its molecular mechanisms of function by identifying binding partners and downstream targets in normal NSCs and brain tumor stem cells.  We are also developing novel small molecule inhibitors to block YAP1 function.

 

Yap1 promotes medulloblastoma stem cell maintenance while simultaneously suppressing their differentiation




Our Program Faculty
Jun Li, MD, PhD, FANA, FAAN

Kyuson Yun, PhD
Associate Member, Research Institute
Associate Professor of Neurology
Stanley H. Appel Department of Neurology
Houston Methodist
Weill Cornell Medical College

Dr. Yun began her independent research career at the Jackson Laboratory in Maine, where she built a research program focused on brain cancer stem cells (CSCs). She utilized her expertise in developmental and stem cell biology, genetics/genomics, and mouse modeling to elucidate fundamental properties of cancer stem cells at the molecular and cellular levels and to identify their unique vulnerabilities to target them for eradication.

 

Read More
Her lab identified several novel regulators of brain cancer stem cells and mechanistic studies of those molecules led her to explore the link between cancer stem cells and immune modulation. Since moving to Methodist, her laboratory performed extensive single cell analysis from human glioma patients to elucidate the cellular heterogeneity and cell:cell communication among cancer and immune cells, particularly myeloid cells, that promote immune evasion and tumor progression. Yun laboratory is currently translating these findings by developing therapeutic antibodies and small molecules against dual regulators of cancer stem cells and immune suppressive microenvironment.

Dr. Yun serves as a member of the Scientific Advisory Board of the American Brain Tumor Association and an editorial board member for Scientific Reports. She reviews for top journals in her field and grants applications for US and international government agencies (NIH, DoD, NSF, MRC (UK), Italian Ministry) as well as many foundations. Outside of the lab, she can be found walking around Rice University listening to various entrepreneurial and scientific podcasts. 
Fransisca Leonard, PhD, Research Scientist
Fransisca joined Dr. Yun’s lab as Research Scientist in 2023. Her research focuses on nanomedicine design using polymeric and lipid nanoparticle platforms for macrophage modulation via in vivo targeted CRISPR editing in various inflammatory conditions. She has also developed several disease‐specific 3D in vitro models for drug screening and assessing treatment efficacy metrics. She is very excited to join the team and aim to develop brain-targeting nano formulations for treating neurological diseases and brain injury. In her free time she enjoys crafting and woodworking, as well as exploring playgrounds with her husband and 1.5 year old daughter.
Nourhan Abdelfattah, PhD, Postdoctoral Fellow
Dr. Nourhan Abdelfattah received her PhD from UT Health San Antonio in Cancer Biology in 2018. Her dissertation was focused on identifying microRNAs that enhance the efficacy of chemo- and radiotherapy against pediatric medulloblastoma. She joined Yun’s laboratory as a postdoctoral fellow in May 2018 to continue her training in pediatric brain tumor research. In the Yun lab, she is studying the role of Yap1 in the immune microenvironment of medulloblastoma using genetically engineered mouse models. Outside of the lab Nour enjoys spending time with her daughter, drawing, swimming and reading.
Chihiro Hashimoto, MS, Research Assistant
Chihiro graduated from Tohoku Pharmaceutical University in Japan with a master’s degree in Pharmaceutical Sciences. She then worked for five years as a staff member with the Division of Regulatory Affairs at Fuso Pharmaceutical Industries in Japan. She moved to the United States in 2016 and joined Department of Nanomedicine in HMRI in 2021 as a research assistant II. Eventually she hopes to attain a PhD in biostatistics. She is obsessed with sweets all over the world and her free time is spent with her husband seeking good café and pastry shops in Houston area.
Jia-Shiun Leu, PhD, Postdoctoral Fellow
Dr. Leu obtained his doctoral degree in the Institute of Microbiology and Immunology at National Yang-Ming University, Taiwan. His doctoral thesis was focused on the relationship among genetic factors, host innate immunity, and tuberculosis. Later, he joined MD Anderson Cancer Center to study the post-translational gene regulation and immune-associated microenvironment in brain cancer. He joined Yun’s lab in January 2019 and works on the role of S100A4 in the microenvironment of glioblastoma. Outside of the lab, he enjoys baseball games, exercise, and movies.
Nhat Tran, B.S. Research Assistant
Nhat received his Bachelor of Science degree in Biochemistry from the University of Texas at Austin. As an undergraduate research assistant, he helped optimizing the brightness the mitochondrial NAD+ biosensor of Dr. Xiaolu Cambronne's lab by site-directed mutagenesis. He joined the Yun Lab in 2022 to continue his learning path to expand his knowledge in tumor biology and gain more research experience. He plans on enrolling in a PhD program in 2024. Outside of the lab, he enjoys trying out new food around Houston area and taking pictures of the city with his film camera.
Jose Maldonado, Research Assistant
Jose received his Bachelor of Science degree in Biochemistry from the University of Texas at Austin. As an undergraduate research assistant, he developed multimodal approaches aimed at curtailing biofilm growth models. This included a material methods approach using dendrimer encapsulated nanoparticles and an ionizing radiation approach meant to be implemented in surgical tools. He joined the Yun lab in 2020 to further enrich his background of the interplay between immunology, neurology, and oncology and plans to enroll in a PhD program in 2022. When not in the lab, he tries his hand at amateur astronomy by visiting dark sky sites around Texas with his Dobsonian.
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