Glia cells, myelination, tumorigenesis and cancer neuroscience

Recent studies indicate a convergence between neural developmental processes, neurological disorders and brain tumorigenesis whereby insight into one yields insight into the others. We are interested in understanding how distinct glial cell types (e.g., myelinating oligodendrocytes) and their stem / progenitor cells contribute to neurological diseases and how dysregulated developmental programs play a role in tumorigenesis both in the central (CNS) and peripheral (PNS) nervous systems.

A major focus of our lab is to elucidate the transcriptional, posttranscriptional, epigenetic, and signaling networks that govern development, remyelination, and tumor formation in the CNS and PNS. We have established a series of in vitro and in vivo animal models to understand the mechanisms underlying myelinogenesis and neurodegenerative diseases such as multiple sclerosis and autism spectrum disorder, as well as brain tumorigenesis by using endogenous and patient-derived brain or neural tumor models that recapitulate histological and molecular features of human tumors.

We use cutting-edge molecular and cellular approaches (e.g., single-cell multi-omics, functional genomics, and spatial transcriptomics) to dissect how the genetic, epigenetic, and microenvironment controls brain or neural cancer development, recurrence, and metastasis. Our cross-species genomic analyses of human tumors and developing brain tissue at the single cell resolution coupled with genetic mouse modeling have identified a set of glial progenitor-like cells (e.g., Olig2+ pri-OPCs) and “stem-like’ cells (e.g., transitional cerebellar progenitors) as key in the formation of malignant gliomas and medulloblastoma, respectively, pointing to specific cell lineages as the origin of distinct brain tumors, and potential lineage-specific vulnerabilities for targeting distinct subtypes of brain tumors. We are also investigating the tumor microenvironment control of cancer stem cell fitness, tumor recurrence and metastasis by using lineage-traceable model systems for developing effective immunotherapy.

Current projects in Lu Lab aim to: 

  1. Leverage cutting-edge genomic and multi-omics approaches to dissect the brain tumor cells of origin and underlying molecular and signaling pathways that are hijacked and altered during the evolution of brain cancers including glioblastoma, medulloblastoma, ependymoma, and diffuse midline gliomas (DMG / DIPG) (Luo et al., Nature, 2022; Hu et al., Nature Cell Biology, 2023; Weng et al., Cell Stem Cell, 2019; Zhang et al., Cancer Cell, 2019; Lu et al., Cancer Cell, 2016, He et al., Nature medicine, 2014).
  2. Define transcriptional, signaling, and epigenetic control of myelination and functional nerve regeneration by using in vitro primary neural cell culture, genetically-engineered mice, and pharmacogenomic approaches (Yu et al., Cell, 2013; Wang, et al., Science Advances, 2020; He et al., Nature medicine, 2018; Zhao et al., Dev Cell 2018; He et al., Neuron, 2017; Wang et al., Dev Cell 2017; He et al., Nature Neuroscience, 2016).
  3. Dissect molecular and signaling mechanisms that control Schwann cell myelination in the PNS and the malignant transformation of peripheral nerve sheath tumors (MPNST) by defining the tumor stem-like subpopulation, tumor cell–state evolution and heterogeneity and their regulatory circuitries during NF-to-MPNST transformation (Wu, et al., Science Advances, 2022; Wu et al., Cancer Cell, 2018; Deng et al., Nature communications, 2017; Wu et al., Nature Neuroscience, 2016).

Our research goals comprise dissecting the etiological mechanisms of these neurological diseases and cancers to develop effective therapies respectively through promoting myelin repair and functional nerve regeneration or blocking brain tumorigenesis and recurrence.