Announcement
APRIL 26, 2022
Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumor-promoting genes can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). These ecDNA don’t follow the normal “rules” of chromosomal inheritance, enabling tumors to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible, and licensing cancers with a way to evolve and change their genomes to evade treatments, at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed, further contributing to aggressive tumor growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat and cancer patients whose tumors harbor ecDNA have markedly shorter survival. Many questions about ecDNA remain unanswered. How does it form and function? How does it evade the immune system? Can we find its vulnerabilities and target them to benefit patients? The Cancer Grand Challenges Team eDyNAmiC aims to deliver bold collaborations and innovative solutions to interrogate this fundamental aspect of cancer biology and potentially launch a new field of cancer therapeutics.
Working closely with the Howard Chang lab at Stanford, including jointly mentoring trainees, as well as with our colleagues across the world in Team eDyNAmic, we are a model of collaborative science in which are trainees play a lead role in gaining new insights into extrachromosomal DNA and translating them into new treatments for people with some of the hardest-to-treat types of cancer.
Feature Publications
Nature, April 2023
Extrachromosomal DNA in the cancerous transformation of Barrett’s oesophagus
Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer. At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing…
Nature Genetics, November 2022
Targeted profiling of human extrachromosomal DNA by CRISPR-CATCH
Extrachromosomal DNA (ecDNA) is a common mode of oncogene amplification but is challenging to analyze. Here, we adapt CRISPR-CATCH, in vitro CRISPR-Cas9 treatment and pulsed field gel electrophoresis of agarose-entrapped genomic DNA, previously developed for bacterial chromosome segments, to isolate megabase-sized human ecDNAs. We demonstrate…
Nature Genetics, September 2022
The evolutionary dynamics of extrachromosomal DNA in human cancers
Oncogene amplification on extrachromosomal DNA (ecDNA) is a common event, driving aggressive tumor growth, drug resistance and shorter survival. Currently, the impact of nonchromosomal oncogene inheritance—random identity by descent—is poorly understood. Also unclear is the impact of ecDNA on somatic variation and selection. Here integrating theoretical models…
Nature, November 2021
ecDNA hubs drive cooperative intermolecular oncogene expression
Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation. Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs—clusters of around 10–100 ecDNAs…
Nature Reviews Clinical Oncology, September 2022
Leveraging extrachromosomal DNA to fine-tune trials of targeted therapy for glioblastoma: opportunities and challenges
Glioblastoma evolution is facilitated by intratumour heterogeneity, which poses a major hurdle to effective treatment. Evidence indicates a key role for oncogene amplification on extrachromosomal DNA (ecDNA) in accelerating tumour evolution and thus resistance to treatment, particularly in glioblastomas…
Nature Structural & Molecular Biology, August 2022
Gene regulation on extrachromosomal DNA
Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation. Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome. Here we show that ecDNA hubs—clusters of around 10–100 ecDNAs…
Nature, February 2022
Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA
Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions , diffuse hypermutation termed omikli, and longer strand-coordinated events termed kataegis. Here we provide a comprehensive characterization of clustered substitutions…
Celebrating the new journey of our trainees
Recent trainees from the Mischel lab have gone on to successful independent careers in academic medicine and science (David Nathanson, UCLA, Deliang Guo, OSU, David Akhavan KU, Kenta Masui Tokyo Women’s Medical University, Feng Lui Shanghai, Jiaotong University, Tomoo Matsutani, Chiba University, Kazu Tanaka Kobe University, Shiro Ikegami Chiba University, Akio Iwanami, Keio University, Koji Yoshimoto, Chair of Neurosurgery, Kagoshima University, Sihan Wu, UT Southwestern Children's Research Institute, Mathieu Bakhoum, Yale University).
Recent trainees from the Mischel lab have also moved on to exciting Academic and Biotech positions (Junfeng Bi, Assistant Professor, Fudan University, China and Joshua Lange, Scientist, Boundless Bio Company).
Junfeng Bi, PhD
We are thrilled to announce that Junfeng Bi, our previous postdoc scientist, has joined Fudan University, China as Assistant Professor.
Joshua Lange, PhD
Our previous PhD Student Joshua Lange has joined Boundless Bio Company as Research Scientist.
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