About

Matthew Vander Heiden is the Lester Wolfe Professor of Molecular Biology and the Director of the Koch Institute for Integrative Cancer Research at MIT. His research focuses on the role that cell metabolism plays in mammalian physiology, with a particular emphasis on cancer. He studies the biochemical pathways that cells utilize and how these pathways are regulated to meet the metabolic requirements of cells in different physiological situations. His work concentrates on understanding how metabolic pathways support cell proliferation in cancer and aims to translate this understanding into novel cancer therapies. Vander Heiden's contributions to the field have been recognized through awards such as election to the National Academy of Medicine in 2024 and being named a Howard Hughes Medical Institute Faculty Scholar in 2016.

Research topics

• Biology
• Chemistry
• Biochemistry
• Cell biology
• Genetics
• Cancer research
• Medicine
• Endocrinology
• Business
• Pathology
• Immunology
• Neuroscience
• Biotechnology
• Internal medicine
• Bioinformatics
• Computational biology

Selected publications

• Nutrient requirements of organ-specific metastasis in breast cancer

  Nature · 2026-01-07 · 6 citations

  articleOpen accessSenior author

  , yet the factors that determine the organs where cancers can metastasize are incompletely understood. Here we quantify the absolute levels of 124 metabolites in multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different tissue sites. We then asked how tumour growth in different tissues relates to nutrient availability and tumour biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. In addition, we identify purine synthesis as a requirement for tumour growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumour de novo nucleotide synthesis activity. These data suggest that a complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases.

  PublisherDOI

• Abstract A060: Characterizing aneuploid tumor heterogeneity in prostate cancer through single-cell DNA sequencing

  Cancer Research · 2026-01-20

  article

  Abstract Genomic instability is a hallmark of cancer and contributes to disease progression through various mechanisms. DNA copy number variation (CNV) is one of the most significant consequences causing a phenomenon called aneuploidy. Aneuploidy is characterized by an imbalanced genome and is associated with lethal progression in prostate cancer. Currently, sequencing-based CNV analysis is widely used to identify cancer-specific aneuploidy that contribute to tumorigenesis, immune evasion, and disease progression. Performing low-pass whole genome sequencing (LP-WGS) on DNA extracted from bulk tissues or cell cultures, is a convenient approach to use for detecting aneuploidy and focal CNVs. However, conventional bulk LP-WGS methods average genomic signals across thousands of cells, often overlooking tumor heterogeneity and small populations with distinct CNV patterns. To address this limitation, we optimized a microfluid nanowell-based system to analyze aneuploidy patterns at a single-cell level using disassociated tissues and isolated nuclei from prostate samples. This pipeline is compatible with both preclinical models and clinical specimens and can be integrated with other multi-omics platforms to generate multimodal datasets for basic and translational research. By leveraging high-throughput single-cell sequencing technologies, our approach enables direct DNA CNV measurement with high sensitivity at a single-cell resolution. Ultimately, this approach aims to improve the resolution of CNV detection, enhance molecular stratification and enable multimodal data integration for better understanding of clinical prostate cancer samples. Citation Format: Chloe Springer, Faith Kim, Kathryn Echandía-Monroe, Aditi Shirke, Gustavo Guitierrez-Cruz, Madeline Wong, Kun-Lin Ho, Duanduan Ma, Elise G. DeArment, Amina Ali, William D. Figg, Gregory Chesnut, Matthew G. Vander Heiden, Xiaofeng A. Su. Characterizing aneuploid tumor heterogeneity in prostate cancer through single-cell DNA sequencing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr A060.

  PublisherDOI

• Abstract 1788: Cysteine accumulation as a driver of resistance to bortezomib

  Cancer Research · 2026-04-03

  article

  Abstract Covalent drugs targeting key oncogenic drivers are promising cancer therapies, but resistance limits their clinical benefit. Many covalent inhibitors rely on reacting with nucleophilic residues on proteins, and thus we hypothesized that these inhibitors could interact directly with intracellular pools of nucleophiles, like cysteine, diminishing the drug’s efficacy. To investigate the possibility that intracellular cysteine drives resistance to chemotherapies, we performed a high throughput screen of clinically available chemotherapeutics in high and low cysteine conditions. We identified cells to be more resistant to boronic-acid proteasome inhibitors in high cysteine conditions (Bortezomib (Btz) and Ixazomib (Ixa)), but not to the epoxyketone-containing proteasome inhibitor Carfilzomib (Cfz). We confirmed the potential of proteasome inhibitors to react with free cysteine and found that Btz and Ixa both formed a covalent conjugate with cysteine as detected via LC-MS. Upon treating cells with the cysteine-drug conjugate, we find nearly all of the toxicity of the drug has been abolished, supporting the hypothesis that cysteine could be a detoxification mechanism in cells. Using cancer cell lines derived from diverse cancer types, we modulated the cysteine availability and treated cells with two classes of proteasome inhibitors: those with either a boronic-acid or an epoxyketone moiety. In conditions known to increase intracellular cysteine such as high media cystine or co-treatment with the cysteine pro-drug NAC, we found that cells are more resistant to boronic acid-containing inhibitors. Conversely, when we decrease intracellular cysteine levels by co-treating with erastin, an inhibitor of SLC7A11, we measured that cells become more sensitive to Btz and Ixa. In either low or high cysteine, sensitivity to Cfz was unchanged. Collectively, these results indicate that a direct interaction between cysteine with the boronic acid group of Btz and Ixa is responsible for cysteine mediated resistance to these compounds, upstream of proteasome inhibition. We next explored cysteine’s role in rescuing proteasome function by measuring proteasome activity and ubiquitylation in cells. In both assays, we observed that high cysteine prevented the effects of proteosome in cells treated with boronic acid-containing inhibitors. We did not measure a difference in proteasome function in carfilzomib-treated cells in high cysteine, once again implying a unique direct interaction between boronic acid-containing inhibitors and cysteine. In summary, we uncovered a novel mechanism of resistance to boronic acid-containing proteasome inhibitors with straightforward possibilities to reverse resistance. This work has clinical implications for cancer treatment, especially those with ATF4 or NRF2 stabilization which both drive cysteine accumulation in a SLC7A11-dependent manner. Citation Format: Jennifer A. Brain, Sarah M. Chang, Maximilian Kobiesa, Leah G. Rector, Kelli J. Che, Zhaoqi Li, Sky H. Kim, Matthew G. Vander Heiden, Lucas B. Sullivan. Cysteine accumulation as a driver of resistance to bortezomib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1788.

  PublisherDOI

• Intraoperative arteriovenous patient sampling to assess in situ non–small cell lung cancer metabolism

  Journal of Clinical Investigation · 2026-01-27

  articleOpen access

  Here authors report intraoperative sampling of blood entering and leaving the lung allowing direct assessment of nutrient use by lung cancer.

  PublisherOA PDFDOI

• Abstract B064: KDM2-mediated epigenetic mechanism regulates brain metastasis of breast cancer

  Cancer Research · 2026-03-23

  article

  Abstract Metastatic brain tumors are frequently observed in breast cancer patients, particularly those with the HER2+ and triple-negative breast cancer (TNBC) subtypes, and are associated with the shortest disease-specific survival. Despite this clinical observation, specific therapies for brain metastases remain unavailable due to the lack of actionable molecular targets. Here, we focused on the high cellular stress feature in the brain microenvironment and identified a low level of H3K36me2 and high expression of KDM2A H3K36me2 demethylase as key features that contribute to the metastatic fitness of breast cancer cells in the brain. Multiplexed spatial protein analysis on clinical TNBC brain metastasis tissues using the CODEX platform revealed that the low level of H3K36me2 in TNBC cells was associated with a proliferative phenotype and a unique metastatic brain tumor microenvironment. Knockout of KDM2A and its paralog KDM2B preferentially inhibited cellular growth in the cellular stress condition and suppressed brain metastasis outgrowth in a preclinical model. Mechanistically, we identified that KDM2 plays a crucial role in maintaining transcriptional fitness under cellular stress, potentially providing the metastatic fitness advantage in the brain microenvironment. In summary, targeting epigenetic systems presents a promising strategy to control the progression of breast cancer brain metastases. Citation Format: Jun Nishida, Zheqi Li, Marco Seehawer, Kun Huang, Oscar Lin, Shreya Nakhawa, Maxime Meylan, Ye Tian, Graham L. Barlow, Elinor G. Sterner, Xinran Cai, Kimberly A. Parker, Marie-Anne Goyette, Pierre Foidart, Laura Stevens, Ashka Patel, Deborah Dillon, Kai Wucherpfennig, Nancy U. Lin, Matthew G. Vander Heiden, Kornelia Polyak. KDM2-mediated epigenetic mechanism regulates brain metastasis of breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr B064.

  PublisherDOI

• Pre-diagnostic lipid metabolites are enriched in men who develop advanced prostate cancer: a nested case-control study

  medRxiv · 2026-03-13

  articleOpen access

  ABSTRACT Few studies with pre-diagnostic samples have estimated associations between circulating metabolites and risk of advanced prostate cancer. We performed untargeted metabolomic profiling of pre-diagnostic blood samples from 212 advanced prostate cancer cases (stage ≥T3b or lethal during follow-up) and 212 matched controls from the Health Professionals Follow-up Study. 243 metabolites were assayed using liquid chromatography-tandem mass spectrometry (Broad Institute) and met quality control standards. We used multivariable conditional logistic regression to generate odds ratios (OR) and 95% confidence intervals (95%CI) for associations between individual metabolites and risk of advanced prostate cancer, and conducted metabolite set enrichment tests to identify metabolite classes enriched in advanced prostate cancer. Subgroup analyses were conducted by body mass index (BMI) and time between blood draw and diagnosis. Levels of 16 lipid species were nominally associated with advanced prostate cancer at p <0.05, though none were statistically significant after multiple testing correction. The strongest signals were for C56:1 triacylglycerol (TAG; OR: 1.34, 95%CI: 1.07-1.67) and C38:4 diacylglycerol (DAG; OR: 1.27, 95%CI: 1.04-1.55). Enrichment analyses revealed six metabolite classes associated with advanced prostate cancer after multiple testing adjustment, the top four of which were DAGs and TAGs: DAGs overall ( P =3.4E-07), unsaturated DAGs ( P =5.9E-07), unsaturated TAGs ( P =2.3E-06), and TAGs overall ( P =2.4E-06). 43 metabolites were nominally associated with advanced prostate cancer among individuals with BMI <25 kg/m 2 ; only three demonstrated nominal associations in individuals with BMI ≥25 kg/m 2 . These findings suggest associations between circulating pre-diagnostic lipid levels and aggressive prostate cancer risk, particularly in lean individuals.

  PublisherOA PDFDOI

• Ribosome-associated quality control of aberrant protein production during amino acid limitation

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-15

  articleOpen accessSenior authorCorresponding

  Amino acids can become limiting for protein synthesis through depletion of charged tRNAs, leading to ribosome stalling and disruption of translation elongation at specific codons. To assess whether this is a mechanism by which amino acid availability can directly influence gene expression, we designed a reporter library to measure translation disruption across all sense codons in the context of amino acid limitations. We found that arginine limitation consistently impairs translation at the arginine codon AGA, resulting in synthesis of proteins from endogenous transcripts. In contrast, GCN2 pathway activation suppresses translation disruption following depletion of most other amino acids. Genome-wide screens revealed that the ribosome quality control trigger (RQC-T) and RQC pathways, which resolve ribosome collisions on defective mRNAs, catalyze ribosome splitting and premature fall-off in response to arginine depletion. Additionally, the E3 ubiquitin ligase RNF14, recently shown to clear ribosome A-site obstructions, promotes translation disruption through both ribosome fall-off and frameshifting during arginine limitation. Together, these data show that the RQC machinery is engaged by tRNA-limited ribosomes and identify a new role for RNF14 as a regulator of translation upon arginine limitation.

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• Unterstützung evidenzinformierter Entscheidungs- und Lernprozesse im ÖGD auf kommunaler Ebene

  Das Gesundheitswesen · 2026-04-01

  articleSenior author
  PublisherDOI

• Aconitase 2 the rescue: A safeguard against excess mitochondrial citrate

  Molecular Cell · 2026-05-01

  articleSenior author
  PublisherDOI

• Abstract B017: Multiomic single-cell profiling of a novel MYC-driven mouse prostate cancer model

  Cancer Research · 2026-01-20

  article

  Abstract MYC overexpression, often associated with chromosome 8q24 amplification, is a well identified genetic alteration in aggressive prostate cancer, especially in metastatic castration-resistant prostate cancer (mCRPC). It has been reported that MYC amplification counteracts with androgen receptor (AR) signaling, which has significant impacts on androgen deprivation therapy efficacy. In this study, we developed a prostate cancer mouse model in which MYC overexpression is initially induced by AR but AR-independent during tumorigenesis and progression. We employed the Multiome technology integrating single-cell RNA-sequencing (scRNA-seq) and ATAC-sequencing (scATAC-seq) to profile late-stage MYC-driven non-metastatic and metastatic prostate cancers. Consistent with previous studies using AR-dependent MYC-driven models, we identified that primary tumors are composed of a large quantity of luminal cells. We have also observed a higher proportion of luminal cells in the tumors that developed metastasis, while localized primary tumors were more abundant in basal cells, and transitional cell types. Interestingly, we uncovered heterogeneous transitional populations featured by different cell cycle profiles and cell-type gene signatures. With gene set enrichment analysis (GSEA), we identified differential enrichment of inflammatory pathways in luminal cells in metastatic primary tumors relative to localized primary tumors. By integrating with scATAC-seq analysis, we also identified new differential transcriptional and epigenetic regulators that may drive the aggressiveness of these MYC-driven cancers in a tissue specific manner. In addition, we applied inferred copy number variation (CNV) analysis and showed that aggressive tumors and metastasis harbor higher levels of CNVs. Together, these findings reveal how MYC overexpression reshapes prostate epithelial lineage, chromatin landscape and genomic instability to promote AR-independent aggressiveness, providing mechanistic insights and a foundation for future therapeutic targeting of MYC-driven malignancies. Citation Format: Kathryn Echandía-Monroe, Sofia Hu, Daniel R. Schmidt, Kun-Lin Ho, Duanduan Ma, Elise G. DeArment, Faith Kim, Chloe Springer, Savannah Washburn, Madeline M. Wong, Kate Lu, Marianna Trakala, William D. Figg, Matthew G. Vander Heiden, Xiaofeng A. Su. Multiomic single-cell profiling of a novel MYC-driven mouse prostate cancer model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B017.

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Recent grants

• NIH Grant R03MH085679

  NIH · $25k · 2011

• NIH Grant R21CA198028

  NIH · $371k · 2017

• NIH Grant R01CA201276

  NIH · $3.0M · 2022

• Understanding the role of metabolism in cancer

  NIH · $5.8M · 2019–2026

• Integrated Genomics and Bioinformatics

  NIH · $37.6M · 1997–2027

Frequent coauthors

• Lewis C. Cantley

  Dana-Farber Cancer Institute

  348 shared

• Clary B. Clish

  Harvard University

  191 shared

• Shawn M. Davidson

  Princeton University

  171 shared

• Jared R. Mayers

  Rocky Vista University

  165 shared

• Sarah‐Maria Fendt

  VIB-KU Leuven Center for Cancer Biology

  142 shared

• Craig J. Thomas

  134 shared

• Gary Bellinger

  124 shared

• Caroline A. Lewis

  Guardant (United States)

  121 shared

Labs

• Vander Heiden LabPI

Awards & honors

• National Academy of Medicine, 2024
• Howard Hughes Medical Institute Faculty Scholar, 2016
• SU2C Innovative Research Grant Recipient, 2016