Xie Laboratory

Dr. Xie’s research focuses on tumor initiation, recurrence, and metastasis.

Using brain tumors as a model, his lab studies tumor heterogeneity and cell types responsible for therapy resistance and tumor recurrence. The specific areas include:

• Elucidate the role of F3 in neural and cancer stem cells
• Determine the downstream/upstream regulators of neural and cancer stem cells
• Identify and characterize drugs targeting cancer stem cells
• Examine Niche components crucial for cancer stem cells and brain metastases

Current Projects

Brain tumor heterogeneity and tumor initiation mechanism

Brain tumors, especially high-grade glioblastoma multiforme (GBM), are extremely heterogeneous. Understanding how different cell types drive tumor growth, respond to conventional therapies, and contribute to tumor recurrence is crucial for developing targeted, long-lasting treatments. In the laboratory, we use genetically engineered mouse models to study the tumor-initiating potential of different cell types within normal brains. These models employ inducible Cre lines to promote tumor formation from neural stem cells (Nestin, GFAP), various progenitor cells (Ascl1, Ng2, Dlx1, NeuroD1), oligodendrocytes, astrocytes, and neurons, which enable us to explore tumor formation mechanisms and develop targeted treatments.

By incorporating somatic mutations in tumor suppressors like TP53, NF1, PTEN, CDKN2A/B, and oncogenes such as EGFR, PIK3A/CD, and IDH1/2, we simulate different brain tumor subtypes with these Cre transgenic lines. Using single-cell RNA sequencing technology, we have identified six distinct GBM cell types characterized by unique gene signatures. Marker antibodies and transgenes are being applied to isolate these cell types for functional analysis including stemness and tumor-forming capabilities. These efforts aim to uncover the key cell type(s) involved in tumor initiation, drug resistance, and tumor recurrence.

Role of F3 in neural and cancer stem cells.

Our preliminary findings highlight the critical role of stem-like cells in tumor initiation and recurrence. An overlap analysis of various neural and cancer stem cell signatures has identified nine key genes, including F3 (also known as tissue factor or TF), a cell surface protein. Antibodies targeting F3 have been shown to enrich sphere-forming cells, which are more tumorigenic than other tumor cells. The potential role of F3 in tumor initiation and stemness maintenance is currently under investigation.

Self-renewal of neural and cancer stem cells.

The Identification of stem-like cancer cells paves the way for uncovering the upstream and downstream regulators crucial for their function. CRISPR screens are being conducted in mouse and human brain tumor stem cells to elucidate key molecular factors. Additionally, clinical drug libraries are being examined to preferentially target cancer stem cells, with the goal of developing combination therapies that enhance the efficacy of existing chemo- and radiotherapy treatments for brain tumor patients.

Niche components for brain tumor cancer stem cells and brain metastases.

Brain metastases occur in 20% to 40% of cancer patients, making them the most common intracranial tumors in adults. With a five-year survival rate as low as 2.4%, this is a devastating disease. The mechanisms by which metastatic tumor cells disseminate from different organs, migrate to the brain, and establish new colonies remain unclear. Using our physiologically relevant mouse models, niche cells are being isolated before and after tumor induction to manifest the cellular components and signaling pathways involved in brain tumor recurrence and metastasis.

 Publications

Selected Publications

1. High-resolution mouse subventricular zone stem-cell niche transcriptome reveals features of lineage, anatomy, and aging. Xie X, Laks D, Sun DC, Poran A, Laughney AM, Wang ZL, Sam J, Belenguer G, Fariñas I, Elemento O, Zhou XP, Parada LF, Proc Natl Acad Sci U S A. 2020. PMID: 33229571
2. Stem-like cells drive NF1-associated MPNST functional heterogeneity and tumor progression. Sun DC, Xie X, Wang ZL, Sait SF, Iyer SV, Chen YJ, Brown R, Laks D, Chipman M, Parada LF. Cell Stem Cell. 2021 May 11:S1934-5909(21)00187-9. doi: 10.1016/j.stem.2021.04.029.
3. Quiescent human glioblastoma stem cells drive tumor initiation, expansion, and recurrence following chemotherapy. *Xie X, Laks D, Sun DC, Ganbold M, Wang ZL, Pedraza AM, Bale T, Tabar V, Brennan C, Zhou XP, *Parada LF. Dev Cell. 2022 Jan 10;57(1):32-46.e8. doi: 10.1016/j.devcel.2021.12.007. *Corresponding author
4. Glioblastoma functional heterogeneity and enrichment of cancer stem cells with tumor recurrence. *Xie XP, Ganbold M, Li J, Lien M, Chipman ME, Wang T, Jayewickreme CD, Pedraza AM, Bale T, Tabar V, Brennan C, Sun DC, Sharma R, *Parada LF. Neuron. 2024 *Corresponding author