Announcements
MARCH 10, 2025: AACR - American Association for Cancer Research
"Paul Mischel, MD, of Stanford Pathology has been elected 2025 class of Fellows of the AACR Academy for profound contributions to the scientific understanding of the role of extrachromosomal DNA (ecDNA) in cancer development and therapeutic resistance, including the development of innovative techniques to monitor ecDNA segregation during cell division."
PHILADELPHIA – The American Association for Cancer Research (AACR) today announced its newly elected 2025 class of Fellows of the AACR Academy.
The mission of the Fellows of the AACR Academy is to recognize and honor extraordinary scientists whose groundbreaking contributions have driven significant innovation and progress in the fight against cancer. Fellows of the AACR Academy constitute a global brain trust of leading experts...
NOVEMBER 7, 2024: "Outside Influence"
The cover shows circular extrachromosomal DNA (ecDNA) sitting next to a chromosome. ecDNA has a significant effect on the outcome of cancer treatment — it can render tumours resistant to therapies and so contributes to poor outcomes for patients. Several papers in this issue probe the relationship between ecDNA and cancer. In the first, Charles Swanton, Mariam Jamal-Hanjani, Paul Mischel and colleagues present a comprehensive atlas of ecDNA in cancer, mapping its frequency, origin and associations with outcome. In the second paper, Howard Chang, Paul Mischel and co-workers reveal how different ecDNAs in cancer cells can be inherited during cell division and how that can drive cancer. A third paper, by Paul Mischel, Howard Chang, Christian Hassig and colleagues, identifies a potential vulnerability in cancers containing ecDNA that could open the way for treatment. And a fourth paper by Bishoy Faltas and co-workers examines how ecDNA contributes to tumour evolution and therapy resistance in urothelial carcinoma.
APRIL 26, 2022: "eDyNAmiC"
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.
Featured Publications
Nature, November 2024
Origins and impact of extrachromosomal DNA
Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer1,2. Here we examine the diversity of ecDNA elements across cancer, revealing the associated tissue, genetic and mutational contexts. By analysing data from 14,778 patients with 39 tumour types from the 100,000 Genomes Project, we demonstrate that 17.1% of tumour samples contain ecDNA. We reveal a pattern highly indicative of tissue-context-based selection for ecDNAs, linking their genomic content to their tissue of origin. We show that not only is ecDNA a mechanism for amplification of driver oncogenes, but it also a mechanism that frequently amplifies immunomodulatory and inflammatory genes, such as those that modulate lymphocyte-mediated immunity and immune effector processes. Moreover, ecDNAs carrying immunomodulatory genes are associated with reduced tumour T cell infiltration. We identify ecDNAs bearing only enhancers, promoters and lncRNA elements, suggesting the combinatorial power of interactions between ecDNAs in trans. We also identify intrinsic and environmental mutational processes linked to ecDNA, including...
Nature, November 2024
Enhancing transcription–replication conflict targets ecDNA-positive cancers
Extrachromosomal DNA (ecDNA) presents a major challenge for cancer patients. ecDNA renders tumours treatment resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival. At present, there are no ecDNA-specific treatments. Here we show that enhancing transcription–replication conflict enables…
Nature, November 2024
Coordinated inheritance of extrachromosomal DNAs in cancer cells
The chromosomal theory of inheritance dictates that genes on the same chromosome segregate together while genes on different chromosomes assort independently. Extrachromosomal DNAs (ecDNAs) are common in cancer and drive oncogene amplification, dysregulated gene expression and intratumoural heterogeneity through random segregation during cell division. Distinct ecDNA sequences, termed ecDNA species, can co-exist…
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.
ChEM-H Resources
Chemistry/Biology Interface (CBI)
Graduate Training Program
Paul Mischel
Stanford Momentum - The Cartographer of Cancer
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