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- Bonagas, Nadilly, et al.
(författare)
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Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress
- 2022
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Ingår i: NATURE CANCER. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 156-
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Tidskriftsartikel (refereegranskat)abstract
- The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors. Helleday and colleagues describe a nanomolar MTHFD2 inhibitor that causes replication stress and DNA damage accumulation in cancer cells via thymidine depletion, demonstrating a potential therapeutic strategy in AML tumors in vivo.
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- Degasperi, Andrea, et al.
(författare)
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A practical framework and online tool for mutational signature analyses show intertissue variation and driver dependencies
- 2020
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Ingår i: Nature Cancer. - : Springer Science and Business Media LLC. - 2662-1347. ; 1:2, s. 249-263
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Tidskriftsartikel (refereegranskat)abstract
- Mutational signatures are patterns of mutations that arise during tumorigenesis. We present an enhanced, practical framework for mutational signature analyses. Applying these methods to 3,107 whole-genome-sequenced (WGS) primary cancers of 21 organs reveals known signatures and nine previously undescribed rearrangement signatures. We highlight interorgan variability of signatures and present a way of visualizing that diversity, reinforcing our findings in an independent analysis of 3,096 WGS metastatic cancers. Signatures with a high level of genomic instability are dependent on TP53 dysregulation. We illustrate how uncertainty in mutational signature identification and assignment to samples affects tumor classification, reinforcing that using multiple orthogonal mutational signature data is not only beneficial, but is also essential for accurate tumor stratification. Finally, we present a reference web-based tool for cancer and experimentally generated mutational signatures, called Signal (https://signal.mutationalsignatures.com), that also supports performing mutational signature analyses.
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- Duran-Ferrer, Marti, et al.
(författare)
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The proliferative history shapes the DNA methylome of B-cell tumors and predicts clinical outcome
- 2020
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Ingår i: NATURE CANCER. - : Springer Nature. - 2662-1347. ; 1:11, s. 1066-1081
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Tidskriftsartikel (refereegranskat)abstract
- We report a systematic analysis of the DNA methylation variability in 1,595 samples of normal cell subpopulations and 14 tumor subtypes spanning the entire human B-cell lineage. Differential methylation among tumor entities relates to differences in cellular origin and to de novo epigenetic alterations, which allowed us to build an accurate machine learning-based diagnostic algorithm. We identify extensive individual-specific methylation variability in silenced chromatin associated with the proliferative history of normal and neoplastic B cells. Mitotic activity generally leaves both hyper- and hypomethylation imprints, but some B-cell neoplasms preferentially gain or lose DNA methylation. We construct a DNA-methylation-based mitotic clock, called epiCMIT, whose lapse magnitude represents a strong independent prognostic variable in B-cell tumors and is associated with particular driver genetic alterations. Our findings reveal DNA methylation as a holistic tracer of B-cell tumor developmental history, with implications in differential diagnosis and the prediction of clinical outcome. Martin-Subero and colleagues analyze DNA methylation patterns in B-cell tumors and their normal cells of origin, and develop epiCMIT, a methylation-based mitotic clock with prognostic relevance.
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- Ferraro, Gino B., et al.
(författare)
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Fatty acid synthesis is required for breast cancer brain metastasis
- 2021
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Ingår i: Nature Cancer. - : Springer Science and Business Media LLC. - 2662-1347. ; 2:4, s. 414-428
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Tidskriftsartikel (refereegranskat)abstract
- Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2-positive breast cancer and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in the brain. We determine that this phenotype is an adaptation to decreased lipid availability in the brain relative to other tissues, resulting in site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase reduces human epidermal growth factor receptor 2-positive breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.
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- Helleday, T
(författare)
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Polθ inhibitors unchained
- 2021
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Ingår i: Nature cancer. - : Springer Science and Business Media LLC. - 2662-1347. ; 2:6, s. 581-583
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Tidskriftsartikel (refereegranskat)
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| 11. |
- Kepp, O, et al.
(författare)
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Pseudovirus for immunotherapy
- 2020
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Ingår i: Nature cancer. - : Springer Science and Business Media LLC. - 2662-1347. ; 1:9, s. 860-861
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Tidskriftsartikel (refereegranskat)
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| 12. |
- Lehtiö, Janne, et al.
(författare)
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Proteogenomics of non-small cell lung cancer reveals molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms
- 2021
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Ingår i: Nature Cancer. - : Springer Science and Business Media LLC. - 2662-1347. ; 2:11, s. 1224-1242
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Tidskriftsartikel (refereegranskat)abstract
- Despite major advancements in lung cancer treatment, long-term survival is still rare and a deeper understanding of molecular phenotypes would allow the identification of specific cancer dependencies and immune-evasion mechanisms. Here we performed in-depth mass-spectrometry-based proteogenomic analysis of 141 tumors representing all major histologies of non-small cell lung cancer (NSCLC). We identified six distinct proteome subtypes with striking differences in immune cell composition and subtype-specific expression of immune checkpoints. Unexpectedly, high neoantigen burden was linked to global hypomethylation and complex neoantigens mapped to genomic regions, such as endogenous retroviral elements and introns, in immune-cold subtypes. Further, we linked immune evasion with LAG-3 via STK11 mutation-dependent HNF1A activation and FGL1 expression. Finally, we develop a data-independent acquisition mass-spectrometry-based NSCLC subtype classification method, validate it in an independent cohort of 208 NSCLC cases and demonstrate its clinical utility by analyzing an additional cohort of 84 late-stage NSCLC biopsy samples.
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- Lin, Matthew J., et al.
(författare)
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Cancer vaccines: the next immunotherapy frontier
- 2022
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Ingår i: NATURE CANCER. - : NATURE PORTFOLIO. - 2662-1347. ; 3:8, s. 911-926
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Forskningsöversikt (refereegranskat)abstract
- Brody and colleagues discuss the current status and potential of cancer vaccines, highlighting challenges and opportunities to advance promising candidates to the clinic. After several decades, therapeutic cancer vaccines now show signs of efficacy and potential to help patients resistant to other standard-of-care immunotherapies, but they have yet to realize their full potential and expand the oncologic armamentarium. Here, we classify cancer vaccines by what is known of the included antigens, which tumors express those antigens and where the antigens colocalize with antigen-presenting cells, thus delineating predefined vaccines (shared or personalized) and anonymous vaccines (ex vivo or in situ). To expedite clinical development, we highlight the need for accurate immune monitoring of early trials to acknowledge failures and advance the most promising vaccines.
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| 18. |
- Tamborero, D, et al.
(författare)
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The Molecular Tumor Board Portal supports clinical decisions and automated reporting for precision oncology
- 2022
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Ingår i: Nature cancer. - : Springer Science and Business Media LLC. - 2662-1347. ; 3:2, s. 251-
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Tidskriftsartikel (refereegranskat)abstract
- There is a growing need for systems that efficiently support the work of medical teams at the precision-oncology point of care. Here, we present the implementation of the Molecular Tumor Board Portal (MTBP), an academic clinical decision support system developed under the umbrella of Cancer Core Europe that creates a unified legal, scientific and technological platform to share and harness next-generation sequencing data. Automating the interpretation and reporting of sequencing results decrease the need for time-consuming manual procedures that are prone to errors. The adoption of an expert-agreed process to systematically link tumor molecular profiles with clinical actions promotes consistent decision-making and structured data capture across the connected centers. The use of information-rich patient reports with interactive content facilitates collaborative discussion of complex cases during virtual molecular tumor board meetings. Overall, streamlined digital systems like the MTBP are crucial to better address the challenges brought by precision oncology and accelerate the use of emerging biomarkers.
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