Dr. Aparna Bhaduri's Research at UCLA: Unraveling the Mysteries of Brain Development and Cancer

Dr. Aparna Bhaduri is an Assistant Professor of Biological Chemistry in the David Geffen School of Medicine at UCLA. Her lab studies human brain development and brain cancer, two processes that are more connected than they might seem. She investigates how the many different cell types in the brain arise and explores why certain developmental mechanisms reappear later in life in aggressive brain cancers. Her work bridges human brain development and cancer research.

Academic Background and Training

Dr. Aparna Bhaduri earned a B.S. in Biochemistry and Cell Biology and a B.A. in Political Science from Rice University in 2010. She completed her doctoral studies at Stanford University in Cancer Biology in 2016, where she focused on epithelial tissue differentiation and neoplasms. She was a postdoctoral scholar at the University of California San Francisco in the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, in the lab of Dr. Arnold Kriegstein. As a postdoctoral scholar, she used single-cell RNA sequencing to characterize cell types in the developing cortex across cortical areas, in human and non-human primates, and in glioblastoma.

Research Focus: Bridging Brain Development and Cancer

The human brain is uniquely complex, largely due to the expansion of specific regions like the cerebral cortex, the outermost, wrinkly layer of the brain responsible for higher-order thinking. What’s fascinating is that most of the cells that make up this structure are generated before birth, during a phase of peak neurogenesis when billions of neurons form each day. These same developmental processes also appear in glioblastoma, the most aggressive form of adult brain cancer. Certain cell types that exist only in the developing brain disappear before birth, only to re-emerge decades later in glioblastoma. The first time they exist, they help build the brain. The second time, they drive cancer. Bhaduri's lab studies how cell types emerge in the developing human brain and in brain cancers.

Her long-term interests to be pursued in her own independent laboratory at UCLA are in understanding how stem cells during cortical development give rise to the human brain, and how aspects of these developmental programs can be hijacked in cancers such as glioblastoma. One aspect of normal development and cancer that particularly interests her is the role of metabolism in regulating cell fate and tissue homeostasis.

Bhaduri established her lab at UCLA in January 2021.

Research Methods and Techniques

In order to explore these questions, the Bhaduri Lab uses single-cell genomics, informatic analysis, and organoid models. The lab works extensively with primary human tissue, cortical organoids, single-cell RNA-sequencing, and other bulk and single-cell -omics technologies. Bhaduri has obtained massive single-cell datasets of the developing human brain and glioblastoma and created strategies to generate insights into cell diversity, evolution, cancer and the fidelity of organoid model systems from single-cell “omics” analysis.

Single-Cell Genomics

Single-cell genomics is employed to examine gene expression in individual cells, uncovering the signals that drive brain formation and fuel tumor development. As a postdoctoral scholar, she used single-cell RNA sequencing to characterize cell types in the developing cortex across cortical areas, in human and non-human primates, and in glioblastoma.

Informatic Analysis

Bioinformatics, which combines biology and computational science, is used to analyze biological data using computational tools, such as algorithms and databases. Bioinformatics helps researchers sift through large amounts of data to understand biological processes, and study genes, proteins and genomes.

Organoid Models

Because experimental manipulations of the developing human cortex will require in vitro models, she has been using similar approaches to compare cells types in organoid models and primary tissues. The lab generates stem cell-derived brain organoids to mimic aspects of development. These organoid models are developed in collaboration with members of the UCLA Broad Stem Cell Research Center to study normal brain development, metabolism and intersections between neural stem cell biology and brain cancer.

Key Research Areas

Glioblastoma Research

The Bhaduri lab studies glioblastoma, a type of brain cancer that is extremely resistant to treatment and often lethal. Various stem cells can give rise to glioblastoma. The diversity within these stem cells may provide multiple routes for glioblastoma to become resistant to treatment. Because glioblastoma stem cell populations include developmental cell types that are rare or absent in rodents, she aims to investigate the role of stem cell diversity in human glioblastoma.

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She will use a novel organoid transplantation model-which are models of the human cortex grown in a dish-paired with approaches that enable experimental exploration of the single-cell lineages of human tumors. She will determine which populations give rise to each cell type observed within a tumor and then characterize the ways in which diverse populations promote resistance to treatment.

Cortical Development

A core focus is understanding how stem cells during cortical development give rise to the human brain.

Cell Fate Specification

The crucial process by which undifferentiated cells receive molecular signals and genetic cues that guide them towards developing into specific cell types with distinct functions. This process is essential for the formation of various tissues and organs during embryonic development and plays a role in tissue regeneration in adults. The process by which stem cells transform into specific, specialized cell types with distinct functions and features.

Metabolism's Role

One aspect of normal development and cancer that particularly interests her is the role of metabolism in regulating cell fate and tissue homeostasis. Her current research interest involves investigating the influence of cell metabolism in cell fate specification during the cortical development.

Thalamocortical Interactions

Claudia Nguyen, a 5th year NSIDP graduate student in the lab, researches thalamocortical interactions during neurodevelopment, using the organoid system to explore extrinsic signals from thalamus involved in cortical patterning. Bhaduri's lab generated a thalamocortical assembloid. An assembloid is a combination of two organoid types, in this case a cortical organoid and a thalamic organoid. The thalamus is the control center of the brain when it is developed and during development sends projections to the cortex; the organoid can model these and are marked in this image in green.

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Lab Members and Their Research Interests

The Bhaduri Lab is composed of graduate students, postdoctoral scholars, and undergraduate students with diverse backgrounds and research interests.

Dr. Weihong: Trained as a developmental neuroscientist, Dr. Weihong's research interest involves molecular mechanisms underlying neural stem cell differentiation. Her current project uses human cortical organoid systems to study neural lineage specification and cancer.
Dr. Patricia Nano: Patricia joined the Bhaduri lab as a postdoctoral scholar dissecting cellular heterogeneity in the human neocortex with single-cell transcriptomic profiling and in vitro neurodevelopmental models.
Ryan: As a graduate student in the Bhaduri lab, Ryan is interested in dissecting the role and mechanism of PTPRZ1 in glioblastoma multiforme (GBM) tumorigenesis, progression and metastasis.
Jessenya Mil: Her current research interest involves investigating the influence of cell metabolism in cell fate specification during the cortical development.
Claudia Nguyen: Claudia researches thalamocortical interactions during neurodevelopment, using the organoid system to explore extrinsic signals from thalamus involved in cortical patterning.
Elisa Fazzari: As a graduate student in the BhadurI Lab, Elisa aims to combine her interests in neuroscience and cancer by using single-cell RNA sequencing approaches to understand mechanisms of cell fate specification in glioblastoma.
Jose Soto: His current research interests involve studying metabolism during cortical development.
Saatvika Nair: Her interests primarily lie in exploring glioblastoma heterogeneity and tumor progression.
Sean Wang: Sean is specifically interested in all things that have to do with neuroscience and cancer.
Matthew Li: He is very passionate about neuroscience research and more particularly, research about brain cancer.
Daria Azizad: Daria primarily studies the cortical organoid metabolism and does bioinformatics projects to investigate cell type through RNA-seq and ATAC-seq data.
Krish: Krish is studying stem cell differentiation into the thalamus and cortical organoids, as well as their interactions.

Publications

Dr. Bhaduri has contributed to several significant publications in leading scientific journals, including:

"Single-Cell Analyses Identify Brain Mural Cells Expressing CD19 as Potential Off-Tumor Targets for CAR-T Immunotherapies" (Cell, 2020)
"Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma" (Cell, 2020)
"Outer Radial Glia-like Cancer Stem Cells Contribute to Heterogeneity of Glioblastoma" (Cell Stem Cell, 2020)
"The Functional Proximal Proteome of Oncogenic Ras Includes mTORC2" (Molecular Cell, 2019)
"Next-generation sequencing of idiopathic multicentric and unicentric Castleman disease and follicular dendritic cell sarcomas" (Blood Advances, 2018)
"Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex" (Science, 2017)
"Single-cell genomics identifies cell type-specific molecular changes in autism" (Science, 2019)
"Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment" (Genome biology, 2017)
"Neuronal vulnerability and multilineage diversity in multiple sclerosis" (Nature, 2019)
"Cell stress in cortical organoids impairs molecular subtype specification" (Nature, 2020)
"Establishing cerebral organoids as models of human-specific brain evolution" (Cell, 2019)
"Human-specific NOTCH2NL genes affect notch signaling and cortical neurogenesis" (Cell, 2018)
"Development and arealization of the cerebral cortex" (Neuron, 2019)
"Single-cell atlas of early human brain development highlights heterogeneity of human neuroepithelial cells and early radial glia" (Nature neuroscience, 2021)
"Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2A" (Nature genetics, 2015)
"UCSC Cell Browser: visualize your single-cell data" (Bioinformatics, 2021)
"An atlas of cortical arealization identifies dynamic molecular signatures" (Nature, 2021)
"Origins and proliferative states of human oligodendrocyte precursor cells" (Cell, 2020)
"Quantitative analysis of mammalian translation initiation sites by FACS‐seq" (Molecular systems biology, 2014)
"The noncoding RNAs SNORD50A and SNORD50B bind K-Ras and are recurrently deleted in human cancer" (Nature genetics, 2016)

Collaboration with the UCLA Broad Stem Cell Research Center

Dr. Bhaduri is a member of the UCLA Broad Stem Cell Research Center. The Broad Stem Cell Research Center fosters a strong research community through working groups and events like the annual symposium, which bring together experts from UCLA and beyond. It is a great opportunity to step away from your own work and learn from others in the field. It’s also been incredible collaborating with our internal community of scientists. She is currently working on a project with fellow center members Drs. Heather Christofk and Harley Kornblum to investigate how different metabolic states impact brain development and whether they contribute to disease. The center has also provided funding to support several of her projects, including a seed grant that allowed her to pursue some higher risk experiments when she didn’t yet have external funding.

Motivation and Inspiration

Dr. Bhaduri is motivated by the opportunity to do challenging and ambitious experiments in the lab. She also enjoys working with students and postdocs, collaborating with them, mentoring them, learning from them and seeing them grow as scientists.

Personal Interests

Outside of the lab, Dr. Bhaduri enjoys indoor rock climbing.

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