A5080151772- Cancer Genomics and Diagnostics
- Advanced Breast Cancer Therapies
- Neurofibromatosis and Schwannoma Cases
- Glioma Diagnosis and Treatment
- DNA Repair Mechanisms
- Inflammasome and immune disorders
- Ubiquitin and proteasome pathways
- interferon and immune responses
- BRCA gene mutations in cancer
- RNA modifications and cancer
- Genomic variations and chromosomal abnormalities
- Meningioma and schwannoma management
- Chromatin Remodeling and Cancer
- Prostate Cancer Treatment and Research
- Cancer-related Molecular Pathways
- PARP inhibition in cancer therapy
- Cancer Mechanisms and Therapy
- Photosynthetic Processes and Mechanisms
- Renal and related cancers
- Viral Infections and Vectors
- Microtubule and mitosis dynamics
- Cancer-related gene regulation
- Neuroblastoma Research and Treatments
University of California, San Francisco
2021-2024
Arc Research Institute
2023-2024
UCSF Helen Diller Family Comprehensive Cancer Center
2021-2024
Palo Alto Institute
2023-2024
National Institutes of Health
2019
National Cancer Institute
2019
Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter activates anticancer stimulator interferon genes (STING) pathway. However, has other catalytic activities molecular cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single-cell RNA-seq, show both cancer...
Abstract Mechanisms specifying cancer cell states and response to therapy are incompletely understood. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas, most common tumors peripheral nervous system. We find schwannomas comprised 2 molecular groups that distinguished by activation neural crest or nerve injury pathways specify tumor architecture immune microenvironment. Moreover, radiotherapy is sufficient for interconversion immune-enriched through metabolic...
Abstract Genomic sequencing of thousands tumors has revealed many genes associated with specific types cancer. Similarly, large scale CRISPR functional genomics efforts have mapped required for cancer cell proliferation or survival in hundreds lines. Despite this, disease subtypes, such as metastatic prostate cancer, there are likely a number undiscovered tumor driver that may represent potential drug targets. To identify genetic dependencies, we performed genome-scale CRISPRi screens...
Outer kinetochore assembly enables chromosome attachment to microtubules and spindle checkpoint (SAC) signaling in mitosis. Aurora B kinase controls by phosphorylating the Mis12 complex (Mis12C) subunit Dsn1. Current models propose Dsn1 phosphorylation relieves autoinhibition, allowing Mis12C binding inner component CENP-C. Using Xenopus laevis egg extracts biochemical reconstitution, we found that autoinhibition of impedes its B. Our data indicate INCENP central region increases enriching...
Extrachromosomal DNA (ecDNA) amplifications are prevalent drivers of human cancers. We show that ecDNAs exhibit elevated structural variants leading to gene fusions produce oncogene fusion transcripts. The long noncoding RNA (lncRNA) PVT1 is the most recurrent variant across cancer genomes, with PVT1-MYC arising frequently on ecDNA. exon 1 predominant 5' partner fused MYC or other oncogenes 3' end. Mechanistic studies demonstrate confers enhanced stability for transcripts, which requires...
ENPP1 expression correlates with poor prognosis in many cancers, and we previously discovered that is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter activates anticancer STING pathway. However, has other catalytic activities molecular cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single cell RNA-seq (scRNA-seq), show overexpression drives primary breast tumor growth metastasis by synergistically dampening...
Abstract Purpose: CDK12 is a cyclin-dependent kinase (CDK) that mutated or amplified in multiple cancers. We previously described subtype of prostate cancer (PC) characterized predominantly by frameshift, loss-of-function mutations CDK12. This exhibits aggressive clinical features. Experimental Design: Using isogenic PC models generated CRISPR/Cas9-mediated inactivation CDK12, we conducted chemical library screen ~1800 FDA-approved drugs. inhibited cyclin K and CDK13 evaluated the effects on...
Abstract Despite the abundance of somatic structural variations (SVs) in cancer, underlying molecular mechanisms their formation remain unclear. Here, we use 6,193 whole-genome sequenced tumors to study contributions transcription and DNA replication collisions genome instability. After deconvoluting robust SV signatures three independent pan-cancer cohorts, detect transcription-dependent replicated-strand bias, expected footprint transcription-replication collision (TRC), large tandem...
Abstract Extrachromosomal DNA (ecDNA), highly amplified circular DNA, is widespread in human cancers and serves as a primary location for oncogene amplification. Due to its dynamic structural rearrangement asymmetric inheritance during cell division, ecDNA increases tumor genome complexity, contributing drug resistance shortened patient survival. Here, we show that ecDNA-mediated genomic amplification associated with transcript fusion events, which are prevalent cancer often lead...
<div>AbstractPurpose:<p>The cyclin-dependent kinase (CDK), CDK12, is mutated or amplified in multiple cancers. We previously described a subtype of prostate cancer characterized predominantly by frameshift, loss-of-function mutations <i>CDK12</i>. This exhibits aggressive clinical features.</p>Experimental Design:<p>Using isogenic models generated CRISPR/Cas9-mediated inactivation <i>CDK12</i>, we conducted chemical library screen ∼1,800...
<p>Supplemental Figures S1-S7</p>
Abstract Somatic structural variations (SVs) are common in cancer. Although a small fraction of SVs breast and ovarian cancers can be attributed to homologous recombination deficiency, the underlying molecular mechanisms for vast majority somatic remain unclear. Here, we focus on roles transcription DNA replication collisions genomic instability Such unavoidable cells since both use same as template. We hypothesized that (TRCs), if not properly repaired, would lead collapsed forks result...
Abstract DNA methylation profiling provides robust classification of nervous system tumors, but mechanisms driving epigenetic identity individual tumor types are incompletely understood. Integrating (n=76), RNA sequencing (n=24), single-cell RNA-sequencing (n=9), and mass cytometry we discovered vestibular schwannomas comprised two groups distinguished by neural crest development pathways or repair regeneration immune infiltration. Analyses preoperative magnetic resonance imaging studies...
Summary Cell state evolution underlies tumor development and response to therapy 1 , but mechanisms specifying cancer cell states intratumor heterogeneity are incompletely understood. Schwannomas the most common tumors of peripheral nervous system treated with surgery ionizing radiation 2–5 . can oscillate in size for many years after radiotherapy 6,7 suggesting treatment may reprogram schwannoma cells or microenvironment. Here we show epigenetic reprogramming shapes cellular landscape...