About

Matthew G. Jones is an Assistant Professor of Biology at MIT who integrates computational and technological advances to decode the molecular processes underlying spatiotemporal tumor evolution, with a focus on genomic instability and extrachromosomal DNA. His research aims to develop innovative computational and technological approaches to uncover the mechanisms of tumor evolution, with the ultimate goal of identifying new therapeutic targets and creating predictive models to monitor tumor initiation and progression. His lab's research focuses on three interrelated goals: investigating the molecular mechanisms underlying the spatiotemporal dynamics of copy-number alterations (particularly extrachromosomal DNA) in cancer populations; developing new computational methods to trace cellular lineages; and elucidating the principles by which tumors are organized over time. To pursue these aims, the lab integrates advances in computation and AI with cutting-edge multi-omic approaches, including single-cell, spatial, and long-read technologies, lineage tracing, and high-resolution imaging. Broadly, their studies aim to reveal generalizable rules governing tumor progression and treatment resistance, enable the predictive modeling of tumors, and inspire new approaches to intercept tumor progression.

Research topics

• Biology
• Computer science
• Computational biology
• Evolutionary biology
• Medicine

Selected publications

• Tree reconstruction guarantees from CRISPR-Cas9 lineage tracing data using Neighbor-Joining

  Genome Research · 2026-05-14

  preprint

  CRISPR-Cas9-based lineage tracing technologies have enabled the reconstruction of single-cell phylogenies from transcriptional readouts. However, developing tree-reconstruction algorithms with theoretical guarantees in this setting is challenging. In this work, we derive a reconstruction algorithm with theoretical guarantees using Neighbor-Joining (NJ) on distances that are moment-matched to estimate the true tree distances. We develop a series of tools to analyze this algorithm and prove its theoretical guarantees. When the parameters of the data generating process are known and there is no missing data, our results align with established results from common evolutionary models, such as Cavender-Farris-Neyman and Jukes-Cantor. However, to account for the realistic case where the parameters of the data generating process are not known and there is missing data, we develop new theory that shows for the first time that it is still possible to obtain reconstruction guarantees in the CRISPR-Cas9 case and in other models of evolution. Empirically, we show on both simulated lineage tracing data and on real data from a mouse model of lung cancer the improved performance of our method as compared to the traditional use of NJ.

  PublisherDOI

• EcDNA-borne structural variants drive oncogenic fusion transcript amplification

  Cell · 2026-01-07 · 3 citations

  articleOpen access

  Extrachromosomal DNA (ecDNA) amplifications are key drivers of human cancers. Here, we show that ecDNAs are major platforms for generating and amplifying oncogene fusion transcripts across diverse cancer types. By integrating analysis of whole-genome and transcriptome sequences from tumor samples and cancer cell lines of a wide variety of tissue types, we reveal that ecDNAs have the highest rate of oncogene fusion events of any copy-number alteration. Focusing on the most common ecDNA fusion hotspot, we find that fusion of the 5' end of the long noncoding RNA gene, PVT1-with exon 1 joined to diverse 3' partners-confers increased RNA stability, potentially via an SRSF1-dependent mechanism, and enhances MYC-dependent transcription and cancer cell survival. These results demonstrate that ecDNA fosters genome instability and frequent oncogene fusion formation in cancer.

  PublisherDOI

• Genetic elements promote retention of extrachromosomal DNA in cancer cells

  Nature · 2025-11-19 · 8 citations

  articleOpen access

  Abstract Extrachromosomal DNA (ecDNA) is a prevalent and devastating form of oncogene amplification in cancer 1,2 . Circular megabase-sized ecDNAs lack centromeres, stochastically segregate during cell division 3–6 and persist over many generations. It has been more than 40 years since ecDNAs were first observed to hitchhike on mitotic chromosomes into daughter cell nuclei, but the mechanism underlying this process remains unclear 3,7 . Here we identify a family of human genomic elements, termed retention elements, that tether episomes to mitotic chromosomes to increase ecDNA transmission to daughter cells. Using Retain-seq, a genome-scale assay that we developed, we reveal thousands of human retention elements that confer generational persistence to heterologous episomes. Retention elements comprise a select set of CpG-rich gene promoters and act additively. Live-cell imaging and chromosome conformation capture show that retention elements physically interact with mitotic chromosomes at regions that are mitotically bookmarked by transcription factors and chromatin proteins. This activity intermolecularly recapitulates promoter–enhancer interactions. Multiple retention elements are co-amplified with oncogenes on individual ecDNAs in human cancers and shape their sizes and structures. CpG-rich retention elements are focally hypomethylated. Targeted cytosine methylation abrogates retention activity and leads to ecDNA loss, which suggests that methylation-sensitive interactions modulate episomal DNA retention. These results highlight the DNA elements and regulatory logic of mitotic ecDNA retention. Amplifications of retention elements promote the maintenance of oncogenic ecDNA across generations of cancer cells, and reveal the principles of episome immortality intrinsic to the human genome.

  PublisherDOI

• Unified molecular approach for spatial epigenome, transcriptome, and cell lineages

  Proceedings of the National Academy of Sciences · 2025-04-18 · 12 citations

  articleOpen access

  Spatial epigenomics and multiomics can provide fine-grained insights into cellular states but their widespread adoption is limited by the requirement for bespoke slides and capture chemistries for each data modality. Here, we present SPatial assay for Accessible chromatin, Cell lineages, and gene Expression with sequencing (SPACE-seq), a method that utilizes polyadenine-tailed epigenomic libraries to enable facile spatial multiomics using standard whole transcriptome reagents. Applying SPACE-seq to a human glioblastoma specimen, we reveal the state of the tumor microenvironment, extrachromosomal DNA copy numbers, and identify putative mitochondrial DNA variants.

  PublisherOA PDFDOI

• <i>Tahoe-100M</i> : A Giga-Scale Single-Cell Perturbation Atlas for Context-Dependent Gene Function and Cellular Modeling

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-24 · 78 citations

  preprintOpen access

  Abstract Building predictive models of the cell requires systematically mapping how perturbations reshape each cell’s state, function, and behavior. Here, we present Tahoe-100M , a giga-scale single-cell atlas of 100 million transcriptomic profiles measuring how each of 1,100 small-molecule perturbations impact cells across 50 cancer cell lines. Our high-throughput Mosaic platform, composed of a highly diverse and optimally balanced “cell village”, reduces batch effects and enables parallel profiling of thousands of conditions at single-cell resolution at an unprecedented scale. As the largest single-cell dataset to date, Tahoe-100M enables artificial-intelligence (AI)-driven models to learn context-dependent functions, capturing fundamental principles of gene regulation and network dynamics. Although we leverage cancer models and pharmacological compounds to create this resource, Tahoe-100M is fundamentally designed as a broadly applicable perturbation atlas and supports deeper insights into cell biology across multiple tissues and contexts. By publicly releasing this atlas, we aim to accelerate the creation and development of robust AI frameworks for systems biology, ultimately improving our ability to predict and manipulate cellular behaviors across a wide range of applications.

  PublisherOA PDFDOI

• Extrachromosomal DNA driven oncogene spatial heterogeneity and evolution in glioblastoma

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-10-25 · 5 citations

  preprintOpen access

  Abstract Oncogene amplification on extrachromosomal DNA (ecDNA) is strongly associated with treatment resistance and shorter survival for patients with cancer, including patients with glioblastoma. The non-chromosomal inheritance of ecDNA during cell division is a major contributor to intratumoral genetic heterogeneity. At present, the spatial dynamics of ecDNA, and the impact on tumor evolutionary trajectories, are not well understood. Here, we investigate the spatial-temporal evolution of ecDNA and its clinical impact by analyzing tumor samples from 94 treatment-naive human IDH -wildtype glioblastoma patients. We developed a spatial-temporal computational model of ecDNA positive tumors (‘SPECIES’) that integrates whole-genome sequencing, multi-region DNA FISH, and nascent RNAscope, to provide unique insight into the spatial dynamics of ecDNA evolution. Random segregation in combination with positive selection of ecDNAs induce large, predictable spatial patterns of cell-to-cell ecDNA copy number variation that are highly dependent on the oncogene encoded on the circular DNA. EGFR ecDNAs often reach high mean copy number (mean of 50 copies per tumor cell), are under strong positive selection (mean selection coefficient, s &gt; 2) and do not co-amplify other oncogenes on the same ecDNA particles. In contrast, PDGFRA ecDNAs have lower mean copy number (mean of 15 copies per cell), are under weaker positive selection and frequently co-amplify other oncogenes on the same ecDNA. Evolutionary modeling suggests that EGFR ecDNAs often accumulate prior to clonal expansion. EGFR structural variants, including vIII and c-terminal deletions are under strong positive selection, are found exclusively on ecDNA, and are intermixed with wild-type EGFR ecDNAs. Simulations show EGFRvIII ecDNA likely arises after ecDNA formation in a cell with high wild-type EGFR copy number (&gt; 10) before the onset of the most recent clonal expansion. This remains true even in cases of co-selection and co-amplification of multiple oncogenic ecDNA species in a subset of patients. Overall, our results suggest a potential time window in which early ecDNA detection may provide an opportunity for more effective intervention. Highlights ecDNA is the most common mechanism of focal oncogene amplification in IDH wt glioblastoma. EGFR and its variants on ecDNA are particularly potent, likely arising early in tumor development, providing a strong oncogenic stimulus to drive tumorigenesis. Wild-type and variant EGFR ecDNA heteroplasmy (co-occurrence) is common with EGFR vIII or c-terminal deletions being derived from EGFR wild-type ecDNA prior to the most recent clonal expansion. Tumors with ecDNA amplified EGFR versus PDGFRA exhibit different evolutionary trajectories. SPECIES model can infer spatial evolutionary dynamics of ecDNA in cancer. A delay between ecDNA accumulation and subsequent oncogenic mutation may give a therapeutic window for early intervention.

  PublisherOA PDFDOI

• Deciphering cell states and genealogies of human haematopoiesis

  Nature · 2024-01-22 · 124 citations

  articleOpen access

  Abstract The human blood system is maintained through the differentiation and massive amplification of a limited number of long-lived haematopoietic stem cells (HSCs) 1 . Perturbations to this process underlie diverse diseases, but the clonal contributions to human haematopoiesis and how this changes with age remain incompletely understood. Although recent insights have emerged from barcoding studies in model systems 2–5 , simultaneous detection of cell states and phylogenies from natural barcodes in humans remains challenging. Here we introduce an improved, single-cell lineage-tracing system based on deep detection of naturally occurring mitochondrial DNA mutations with simultaneous readout of transcriptional states and chromatin accessibility. We use this system to define the clonal architecture of HSCs and map the physiological state and output of clones. We uncover functional heterogeneity in HSC clones, which is stable over months and manifests as both differences in total HSC output and biases towards the production of different mature cell types. We also find that the diversity of HSC clones decreases markedly with age, leading to an oligoclonal structure with multiple distinct clonal expansions. Our study thus provides a clonally resolved and cell-state-aware atlas of human haematopoiesis at single-cell resolution, showing an unappreciated functional diversity of human HSC clones and, more broadly, paving the way for refined studies of clonal dynamics across a range of tissues in human health and disease.

  PublisherDOI

• CoRAL accurately resolves extrachromosomal DNA genome structures with long-read sequencing

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-02-16 · 2 citations

  preprintOpen access

  Extrachromosomal DNA (ecDNA) is a central mechanism for focal oncogene amplification in cancer, occurring in approximately 15% of early stage cancers and 30% of late-stage cancers. EcDNAs drive tumor formation, evolution, and drug resistance by dynamically modulating oncogene copy-number and rewiring gene-regulatory networks. Elucidating the genomic architecture of ecDNA amplifications is critical for understanding tumor pathology and developing more effective therapies. Paired-end short-read (Illumina) sequencing and mapping have been utilized to represent ecDNA amplifications using a breakpoint graph, where the inferred architecture of ecDNA is encoded as a cycle in the graph. Traversals of breakpoint graph have been used to successfully predict ecDNA presence in cancer samples. However, short-read technologies are intrinsically limited in the identification of breakpoints, phasing together of complex rearrangements and internal duplications, and deconvolution of cell-to-cell heterogeneity of ecDNA structures. Long-read technologies, such as from Oxford Nanopore Technologies, have the potential to improve inference as the longer reads are better at mapping structural variants and are more likely to span rearranged or duplicated regions. Here, we propose CoRAL (Complete Reconstruction of Amplifications with Long reads), for reconstructing ecDNA architectures using long-read data. CoRAL reconstructs likely cyclic architectures using quadratic programming that simultaneously optimizes parsimony of reconstruction, explained copy number, and consistency of long-read mapping. CoRAL substantially improves reconstructions in extensive simulations and 9 datasets from previously-characterized cell-lines as compared to previous short-read-based tools. As long-read usage becomes wide-spread, we anticipate that CoRAL will be a valuable tool for profiling the landscape and evolution of focal amplifications in tumors.

  PublisherOA PDFDOI

• PERCEPTION predicts patient response and resistance to treatment using single-cell transcriptomics of their tumors

  Nature Cancer · 2024-04-18 · 93 citations

  article
  PublisherDOI

• Abstract PR014: PVT1 fusion on extrachromosomal DNA (ecDNA) increases oncogene RNA stability and cancer cell growth

  Molecular Cancer Therapeutics · 2024-11-14

  article

  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 and asymmetric inheritance during cell division, ecDNA increases tumor genome complexity, contributing to drug resistance and shortened patient survival. Here, we show that ecDNA-mediated genomic amplification is highly associated with transcript fusion events, which are prevalent in cancer and often lead to tumor development. We discovered that transcripts with the highest fusion events originate from genes amplified on ecDNA across ecDNA(+) cell lines. Notably, PVT1 (Plasmacytoma Variant Translocation 1) long noncoding RNA, which is known to be a hotspot for chromosomal translocation, is the most frequently fused RNA species in MYC/PVT1-amplified ecDNA(+) cancer cells. Exon 1 of PVT1 is the predominant fusion partner and confers RNA stability, increasing the RNA abundance of the partner oncogene. Using a model cell line with PVT1-MYC fusion on ecDNA, we found that RNA expression of PVT1-MYC increases in vivo in an ecDNA-dependent manner, while canonical MYC does not show a prominent increase. Additionally, ectopic expression of PVT1- MYC in MYC-depleted cancer cells provides higher rescue efficiency than canonical MYC. In contrast, a PVT1-MYC mutant that is unable to enhance RNA stability fails to rescue, highlighting the functional significance of PVT1-mediated RNA stabilization in cancer. This study unveils the link between PVT1 fusion and ecDNA in cancer, providing insights for developing diagnostic and therapeutic approaches tailored to target ecDNA. Citation Format: Hyerim Yi, Shu Zhang, Matthew G Jones, Julia A Belk, Jason Swinderman, Quanming Shi, Ellis J Curtis, Vishnu P Kanakaveti, Paul S Mischel, Howard Y Chang. PVT1 fusion on extrachromosomal DNA (ecDNA) increases oncogene RNA stability and cancer cell growth [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR014.

  PublisherDOI

Frequent coauthors

• Jonathan S. Weissman

  Whitehead Institute for Biomedical Research

  86 shared

• Nir Yosef

  University of California, Berkeley

  64 shared

• Dian Yang

  Columbia University Irving Medical Center

  62 shared

• Jeffrey J. Quinn

  Beam Therapeutics (United States)

  36 shared

• Xiaojie Qiu

  Whitehead Institute for Biomedical Research

  25 shared

• Trever G. Bivona

  24 shared

• Joseph M. Replogle

  Whitehead Institute for Biomedical Research

  24 shared

• Raymond Ho

  Washington Poison Center

  24 shared

Education

• Ph.D., Public Administration & Policy, Public Administration

  Portland State University

  2008

• Master of Public Administration, Public Administration

  Portland State University

  2004

• B.A., Criminal Justice

  Norwich University

  1996

Awards & honors

• Keynote Speaker at Cancer Genetics and Epigenetics Gordon Re…
• Cancer Grand Challenges Future Leaders Conference Best Talk…
• NCI K99/R00 Early-Career Pathway to Independence Award, 2024
• UCSF Discovery Fellow, 2019