Publications by authors named "Giovanni Ciriello"

52 Publications

Cell-autonomous inflammation of BRCA1-deficient ovarian cancers drives both tumor-intrinsic immunoreactivity and immune resistance via STING.

Cell Rep 2021 Jul;36(3):109412

Ludwig Institute for Cancer Research, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.

In this study, we investigate mechanisms leading to inflammation and immunoreactivity in ovarian tumors with homologous recombination deficiency (HRD). BRCA1 loss is found to lead to transcriptional reprogramming in tumor cells and cell-intrinsic inflammation involving type I interferon (IFN) and stimulator of IFN genes (STING). BRCA1-mutated (BRCA1) tumors are thus T cell inflamed at baseline. Genetic deletion or methylation of DNA-sensing/IFN genes or CCL5 chemokine is identified as a potential mechanism to attenuate T cell inflammation. Alternatively, in BRCA1 cancers retaining inflammation, STING upregulates VEGF-A, mediating immune resistance and tumor progression. Tumor-intrinsic STING elimination reduces neoangiogenesis, increases CD8 T cell infiltration, and reverts therapeutic resistance to dual immune checkpoint blockade (ICB). VEGF-A blockade phenocopies genetic STING loss and synergizes with ICB and/or poly(ADP-ribose) polymerase (PARP) inhibitors to control the outgrowth of Trp53Brca1 but not Brca1 ovarian tumors in vivo, offering rational combinatorial therapies for HRD cancers.
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http://dx.doi.org/10.1016/j.celrep.2021.109412DOI Listing
July 2021

The many faces of cancer evolution.

iScience 2021 May 11;24(5):102403. Epub 2021 May 11.

Department of Surgery and Cancer, Imperial College London, London, UK.

Cancer cells acquire genotypic and phenotypic changes over the course of the disease. A minority of these changes enhance cell fitness, allowing a tumor to evolve and overcome environmental constraints and treatment. Cancer evolution is driven by diverse processes governed by different rules, such as discrete and irreversible genetic variants and continuous and reversible plastic reprogramming. In this perspective, we explore the role of cell plasticity in tumor evolution through specific examples. We discuss epigenetic and transcriptional reprogramming in "disease progression" of solid tumors, through the lens of the epithelial-to-mesenchymal transition, and "treatment resistance", in the context endocrine therapy in hormone-driven cancers. These examples offer a paradigm of the features and challenges of cell plastic evolution, and we investigate how recent technological advances can address these challenges. Cancer evolution is a multi-faceted process, whose understanding and harnessing will require an equally diverse prism of perspectives and approaches.
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http://dx.doi.org/10.1016/j.isci.2021.102403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131323PMC
May 2021

Histone acetylation dynamics modulates chromatin conformation and allele-specific interactions at oncogenic loci.

Nat Genet 2021 05 10;53(5):650-662. Epub 2021 May 10.

Swiss Institute for Experimental Cancer Research, School of Life Sciences, EPFL, Lausanne, Switzerland.

In cancer cells, enhancer hijacking mediated by chromosomal alterations and/or increased deposition of acetylated histone H3 lysine 27 (H3K27ac) can support oncogene expression. However, how the chromatin conformation of enhancer-promoter interactions is affected by these events is unclear. In the present study, by comparing chromatin structure and H3K27ac levels in normal and lymphoma B cells, we show that enhancer-promoter-interacting regions assume different conformations according to the local abundance of H3K27ac. Genetic or pharmacological depletion of H3K27ac decreases the frequency and the spreading of these interactions, altering oncogene expression. Moreover, enhancer hijacking mediated by chromosomal translocations influences the epigenetic status of the regions flanking the breakpoint, prompting the formation of distinct intrachromosomal interactions in the two homologous chromosomes. These interactions are accompanied by allele-specific gene expression changes. Overall, our work indicates that H3K27ac dynamics modulates interaction frequency between regulatory regions and can lead to allele-specific chromatin configurations to sustain oncogene expression.
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http://dx.doi.org/10.1038/s41588-021-00842-xDOI Listing
May 2021

Systematic inference and comparison of multi-scale chromatin sub-compartments connects spatial organization to cell phenotypes.

Nat Commun 2021 05 10;12(1):2439. Epub 2021 May 10.

Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.

Chromatin compartmentalization reflects biological activity. However, inference of chromatin sub-compartments and compartment domains from chromosome conformation capture (Hi-C) experiments is limited by data resolution. As a result, these have been characterized only in a few cell types and systematic comparisons across multiple tissues and conditions are missing. Here, we present Calder, an algorithmic approach that enables the identification of multi-scale sub-compartments at variable data resolution. Calder allows to infer and compare chromatin sub-compartments and compartment domains in >100 cell lines. Our results reveal sub-compartments enriched for poised chromatin states and undergoing spatial repositioning during lineage differentiation and oncogenic transformation.
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http://dx.doi.org/10.1038/s41467-021-22666-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110550PMC
May 2021

Cancer cells retrace a stepwise differentiation program during malignant progression.

Cancer Discov 2021 Apr 28. Epub 2021 Apr 28.

Swiss Inst. for Exp. Cancer Res. (ISREC)

Pancreatic Neuroendocrine Tumors (PanNETs) comprise two molecular subtypes, relatively benign islet tumors (IT) and invasive, metastasis-like primary (MLP) tumors. Hitherto, the origin of aggressive MLP tumors has been obscure. Herein, using multi-omics approaches, we revealed that MLP tumors arise from IT via dedifferentiation following a reverse trajectory along the developmental pathway of islet B-cells, which results in the acquisition of a progenitor-like molecular phenotype. Functionally, the microRNA-181cd cluster induces the IT-to-MLP transition by suppressing expression of the Meis2 transcription factor, leading to upregulation of a developmental transcription factor, Hmgb3. Notably, the IT-to-MLP transition constitutes a distinct step of tumorigenesis and is separable from the classical proliferation-associated hallmark, temporally preceding accelerated proliferation of cancer cells. Furthermore, PanNET patients with elevated HMGB3 expression and an MLP transcriptional signature are associated with higher-grade tumors and worse survival. Overall, our results unveil a new mechanism that modulates cancer cell plasticity to enable malignant progression.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1637DOI Listing
April 2021

Prediction of neo-epitope immunogenicity reveals TCR recognition determinants and provides insight into immunoediting.

Cell Rep Med 2021 Feb 6;2(2):100194. Epub 2021 Feb 6.

Department of Oncology, Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Lausanne, Switzerland.

CD8+ T cell recognition of peptide epitopes plays a central role in immune responses against pathogens and tumors. However, the rules that govern which peptides are truly recognized by existing T cell receptors (TCRs) remain poorly understood, precluding accurate predictions of neo-epitopes for cancer immunotherapy. Here, we capitalize on recent (neo-)epitope data to train a predictor of immunogenic epitopes (PRIME), which captures molecular properties of both antigen presentation and TCR recognition. PRIME not only improves prioritization of neo-epitopes but also correlates with T cell potency and unravels biophysical determinants of TCR recognition that we experimentally validate. Analysis of cancer genomics data reveals that recurrent mutations tend to be less frequent in patients where they are predicted to be immunogenic, providing further evidence for immunoediting in human cancer. PRIME will facilitate identification of pathogen epitopes in infectious diseases and neo-epitopes in cancer immunotherapy.
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http://dx.doi.org/10.1016/j.xcrm.2021.100194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897774PMC
February 2021

The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing.

Nat Cancer 2020 22;1:653-664. Epub 2020 Jun 22.

Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Cancer cells adapt their metabolic activities to support growth and proliferation. However, increased activity of metabolic enzymes is not usually considered an initiating event in the malignant process. Here, we investigate the possible role of the enzyme serine hydroxymethyltransferase-2 (SHMT2) in lymphoma initiation. localizes to the most frequent region of copy number gains at chromosome 12q14.1 in lymphoma. Elevated expression of cooperates with in lymphoma development; loss or inhibition of impairs lymphoma cell survival. SHMT2 catalyzes the conversion of serine to glycine and produces an activated one-carbon unit that can be used to support -adenosyl methionine synthesis. SHMT2 induces changes in DNA and histone methylation patterns leading to promoter silencing of previously uncharacterized mutational genes, such as and Together, our findings reveal that amplification of in cooperation with is sufficient in the initiation of lymphomagenesis through epigenetic tumor suppressor silencing.
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http://dx.doi.org/10.1038/s43018-020-0080-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872152PMC
June 2020

Nongenetic Evolution Drives Lung Adenocarcinoma Spatial Heterogeneity and Progression.

Cancer Discov 2021 Jun 9;11(6):1490-1507. Epub 2021 Feb 9.

Swiss Cancer Center Leman, Lausanne, Switzerland.

Cancer evolution determines molecular and morphologic intratumor heterogeneity and challenges the design of effective treatments. In lung adenocarcinoma, disease progression and prognosis are associated with the appearance of morphologically diverse tumor regions, termed histologic patterns. However, the link between molecular and histologic features remains elusive. Here, we generated multiomics and spatially resolved molecular profiles of histologic patterns from primary lung adenocarcinoma, which we integrated with molecular data from >2,000 patients. The transition from indolent to aggressive patterns was not driven by genetic alterations but by epigenetic and transcriptional reprogramming reshaping cancer cell identity. A signature quantifying this transition was an independent predictor of patient prognosis in multiple human cohorts. Within individual tumors, highly multiplexed protein spatial profiling revealed coexistence of immune desert, inflamed, and excluded regions, which matched histologic pattern composition. Our results provide a detailed molecular map of lung adenocarcinoma intratumor spatial heterogeneity, tracing nongenetic routes of cancer evolution. SIGNIFICANCE: Lung adenocarcinomas are classified based on histologic pattern prevalence. However, individual tumors exhibit multiple patterns with unknown molecular features. We characterized nongenetic mechanisms underlying intratumor patterns and molecular markers predicting patient prognosis. Intratumor patterns determined diverse immune microenvironments, warranting their study in the context of current immunotherapies..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1274DOI Listing
June 2021

Exploring chromatin conformation and gene co-expression through graph embedding.

Bioinformatics 2020 12;36(Suppl_2):i700-i708

Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy.

Motivation: The relationship between gene co-expression and chromatin conformation is of great biological interest. Thanks to high-throughput chromosome conformation capture technologies (Hi-C), researchers are gaining insights on the tri-dimensional organization of the genome. Given the high complexity of Hi-C data and the difficult definition of gene co-expression networks, the development of proper computational tools to investigate such relationship is rapidly gaining the interest of researchers. One of the most fascinating questions in this context is how chromatin topology correlates with gene co-expression and which physical interaction patterns are most predictive of co-expression relationships.

Results: To address these questions, we developed a computational framework for the prediction of co-expression networks from chromatin conformation data. We first define a gene chromatin interaction network where each gene is associated to its physical interaction profile; then, we apply two graph embedding techniques to extract a low-dimensional vector representation of each gene from the interaction network; finally, we train a classifier on gene embedding pairs to predict if they are co-expressed. Both graph embedding techniques outperform previous methods based on manually designed topological features, highlighting the need for more advanced strategies to encode chromatin information. We also establish that the most recent technique, based on random walks, is superior. Overall, our results demonstrate that chromatin conformation and gene regulation share a non-linear relationship and that gene topological embeddings encode relevant information, which could be used also for downstream analysis.

Availability And Implementation: The source code for the analysis is available at: https://github.com/marcovarrone/gene-expression-chromatin.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa803DOI Listing
December 2020

Sustained androgen receptor signaling is a determinant of melanoma cell growth potential and tumorigenesis.

J Exp Med 2021 Feb;218(2)

Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.

Melanoma susceptibility differs significantly in male versus female populations. Low levels of androgen receptor (AR) in melanocytes of the two sexes are accompanied by heterogeneous expression at various stages of the disease. Irrespective of expression levels, genetic and pharmacological suppression of AR activity in melanoma cells blunts proliferation and induces senescence, while increased AR expression or activation exert opposite effects. AR down-modulation elicits a shared gene expression signature associated with better patient survival, related to interferon and cytokine signaling and DNA damage/repair. AR loss leads to dsDNA breakage, cytoplasmic leakage, and STING activation, with AR anchoring the DNA repair proteins Ku70/Ku80 to RNA Pol II and preventing RNA Pol II-associated DNA damage. AR down-modulation or pharmacological inhibition suppresses melanomagenesis, with increased intratumoral infiltration of macrophages and, in an immune-competent mouse model, cytotoxic T cells. AR provides an attractive target for improved management of melanoma independent of patient sex.
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http://dx.doi.org/10.1084/jem.20201137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596884PMC
February 2021

Discovering functional evolutionary dependencies in human cancers.

Nat Genet 2020 11 28;52(11):1198-1207. Epub 2020 Sep 28.

Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.

Cancer cells retain genomic alterations that provide a selective advantage. The prediction and validation of advantageous alterations are major challenges in cancer genomics. Moreover, it is crucial to understand how the coexistence of specific alterations alters response to genetic and therapeutic perturbations. In the present study, we inferred functional alterations and preferentially selected combinations of events in >9,000 human tumors. Using a Bayesian inference framework, we validated computational predictions with high-throughput readouts from genetic and pharmacological screenings on 2,000 cancer cell lines. Mutually exclusive and co-occurring cancer alterations reflected, respectively, functional redundancies able to rescue the phenotype of individual target inhibition, or synergistic interactions, increasing oncogene addiction. Among the top scoring dependencies, co-alteration of the phosphoinositide 3-kinase (PI3K) subunit PIK3CA and the nuclear factor NFE2L2 was a synergistic evolutionary trajectory in squamous cell carcinomas. By integrating computational, experimental and clinical evidence, we provide a framework to study the combinatorial functional effects of cancer genomic alterations.
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http://dx.doi.org/10.1038/s41588-020-0703-5DOI Listing
November 2020

Cathepsin S Regulates Antigen Processing and T Cell Activity in Non-Hodgkin Lymphoma.

Cancer Cell 2020 05 23;37(5):674-689.e12. Epub 2020 Apr 23.

Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, EPFL, Lausanne, 1015 Switzerland; Swiss Cancer Center Leman (SCCL), Lausanne, 1015 Switzerland. Electronic address:

Genomic alterations in cancer cells can influence the immune system to favor tumor growth. In non-Hodgkin lymphoma, physiological interactions between B cells and the germinal center microenvironment are coopted to sustain cancer cell proliferation. We found that follicular lymphoma patients harbor a recurrent hotspot mutation targeting tyrosine 132 (Y132D) in cathepsin S (CTSS) that enhances protein activity. CTSS regulates antigen processing and CD4 and CD8 T cell-mediated immune responses. Loss of CTSS activity reduces lymphoma growth by limiting communication with CD4 T follicular helper cells while inducing antigen diversification and activation of CD8 T cells. Overall, our results suggest that CTSS inhibition has non-redundant therapeutic potential to enhance anti-tumor immune responses in indolent and aggressive lymphomas.
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http://dx.doi.org/10.1016/j.ccell.2020.03.016DOI Listing
May 2020

Dynamic Emergence of Observed and Hidden Intra-tumor Heterogeneity.

iScience 2019 Nov 10;21:157-167. Epub 2019 Oct 10.

Department of Computational Biology, University of Lausanne, Lausanne, 1015 Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, 1015 Lausanne, Switzerland. Electronic address:

Intra-tumor heterogeneity is frequently observed in cancer patients, and it is associated with therapeutic resistance and disease relapse. However, its systematic assessment is still limited and often unfeasible. Here, we use a mathematical model of tumor progression to decipher how multiple clones emerge and organize into complex architectures. We found a trade-off between cancer cell alteration and proliferation rates that defines a transition between low and high heterogeneity, the latter characterized by branching tumor phylogenies. We predict the existence of observed and hidden intra-tumor heterogeneity, which challenges the correct estimation of intrinsic tumor complexity. Although the numbers of observed and hidden clones do not always correlate, we demonstrate that population frequencies of observed clones can be used to estimate the extent of hidden heterogeneity in both simulated and human tumors. The characterization of complex clonal architectures is a critical first step toward understanding their organizing principles and predicting their emergence.
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http://dx.doi.org/10.1016/j.isci.2019.10.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820272PMC
November 2019

Synaptic proximity enables NMDAR signalling to promote brain metastasis.

Nature 2019 09 18;573(7775):526-531. Epub 2019 Sep 18.

Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland.

Metastasis-the disseminated growth of tumours in distant organs-underlies cancer mortality. Breast-to-brain metastasis (B2BM) is a common and disruptive form of cancer and is prevalent in the aggressive basal-like subtype, but is also found at varying frequencies in all cancer subtypes. Previous studies revealed parameters of breast cancer metastasis to the brain, but its preference for this site remains an enigma. Here we show that B2BM cells co-opt a neuronal signalling pathway that was recently implicated in invasive tumour growth, involving activation by glutamate ligands of N-methyl-D-aspartate receptors (NMDARs), which is key in model systems for metastatic colonization of the brain and is associated with poor prognosis. Whereas NMDAR activation is autocrine in some primary tumour types, human and mouse B2BM cells express receptors but secrete insufficient glutamate to induce signalling, which is instead achieved by the formation of pseudo-tripartite synapses between cancer cells and glutamatergic neurons, presenting a rationale for brain metastasis.
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http://dx.doi.org/10.1038/s41586-019-1576-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6837873PMC
September 2019

The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase.

Cell 2019 08;178(4):807-819.e21

Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

The NRF2 transcription factor controls a cell stress program that is implicated in cancer and there is great interest in targeting NRF2 for therapy. We show that NRF2 activity depends on Fructosamine-3-kinase (FN3K)-a kinase that triggers protein de-glycation. In its absence, NRF2 is extensively glycated, unstable, and defective at binding to small MAF proteins and transcriptional activation. Moreover, the development of hepatocellular carcinoma triggered by MYC and Keap1 inactivation depends on FN3K in vivo. N-acetyl cysteine treatment partially rescues the effects of FN3K loss on NRF2 driven tumor phenotypes indicating a key role for NRF2-mediated redox balance. Mass spectrometry reveals that other proteins undergo FN3K-sensitive glycation, including translation factors, heat shock proteins, and histones. How glycation affects their functions remains to be defined. In summary, our study reveals a surprising role for the glycation of cellular proteins and implicates FN3K as targetable modulator of NRF2 activity in cancer.
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http://dx.doi.org/10.1016/j.cell.2019.07.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693658PMC
August 2019

Publisher Correction: Uncoupling protein 2 reprograms the tumor microenvironment to support the anti-tumor immune cycle.

Nat Immunol 2019 Apr;20(4):515-516

Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland.

In the version of this article initially published, the bars were not aligned with the data points or horizontal axis labels in Fig. 5d, and the labels along each horizontal axis of Fig. 5j-l indicating the presence (+) or absence (-) of doxycycline (Dox) were incorrectly included with the labels below that axis. Also, the right vertical bar above Fig. 7b linking 'P = 0.0001' to the key was incorrect; the correct comparison is αPD-1 versus Dox + αPD-1. Similarly, the right vertical bar above Fig. 7e linking 'P = 0.0002' to the key was incorrect; the correct comparison is αPD-1 versus Rosig + αPD-1. The errors have been corrected in the HTML and PDF versions of the article.
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http://dx.doi.org/10.1038/s41590-019-0359-4DOI Listing
April 2019

EZH2 oncogenic mutations drive epigenetic, transcriptional, and structural changes within chromatin domains.

Nat Genet 2019 03 28;51(3):517-528. Epub 2019 Jan 28.

Swiss Institute for Experimental Cancer Research (ISREC), School of Life Science, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

Chromatin is organized into topologically associating domains (TADs) enriched in distinct histone marks. In cancer, gain-of-function mutations in the gene encoding the enhancer of zeste homolog 2 protein (EZH2) lead to a genome-wide increase in histone-3 Lys27 trimethylation (H3K27me3) associated with transcriptional repression. However, the effects of these epigenetic changes on the structure and function of chromatin domains have not been explored. Here, we found a functional interplay between TADs and epigenetic and transcriptional changes mediated by mutated EZH2. Altered EZH2 (p.Tyr646* (EZH2)) led to silencing of entire domains, synergistically inactivating multiple tumor suppressors. Intra-TAD gene silencing was coupled with changes of interactions between gene promoter regions. Notably, gene expression and chromatin interactions were restored by pharmacological inhibition of EZH2. Our results indicate that EZH2 alters the topology and function of chromatin domains to promote synergistic oncogenic programs.
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http://dx.doi.org/10.1038/s41588-018-0338-yDOI Listing
March 2019

Uncoupling protein 2 reprograms the tumor microenvironment to support the anti-tumor immune cycle.

Nat Immunol 2019 02 21;20(2):206-217. Epub 2019 Jan 21.

Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland.

Immune checkpoint blockade therapy has shifted the paradigm for cancer treatment. However, the majority of patients lack effective responses due to insufficient T cell infiltration in tumors. Here we show that expression of mitochondrial uncoupling protein 2 (UCP2) in tumor cells determines the immunostimulatory feature of the tumor microenvironment (TME) and is positively associated with prolonged survival. UCP2 reprograms the immune state of the TME by altering its cytokine milieu in an interferon regulatory factor 5-dependent manner. Consequently, UCP2 boosts the conventional type 1 dendritic cell- and CD8 T cell-dependent anti-tumor immune cycle and normalizes the tumor vasculature. Finally we show, using either a genetic or pharmacological approach, that induction of UCP2 sensitizes melanomas to programmed cell death protein-1 blockade treatment and elicits effective anti-tumor responses. Together, this study demonstrates that targeting the UCP2 pathway is a potent strategy for alleviating the immunosuppressive TME and overcoming the primary resistance of programmed cell death protein-1 blockade.
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http://dx.doi.org/10.1038/s41590-018-0290-0DOI Listing
February 2019

Comparison of computational methods for the identification of topologically associating domains.

Genome Biol 2018 12 10;19(1):217. Epub 2018 Dec 10.

Department of Computational Biology, University of Lausanne (UNIL), Lausanne, Switzerland.

Background: Chromatin folding gives rise to structural elements among which are clusters of densely interacting DNA regions termed topologically associating domains (TADs). TADs have been characterized across multiple species, tissue types, and differentiation stages, sometimes in association with regulation of biological functions. The reliability and reproducibility of these findings are intrinsically related with the correct identification of these domains from high-throughput chromatin conformation capture (Hi-C) experiments.

Results: Here, we test and compare 22 computational methods to identify TADs across 20 different conditions. We find that TAD sizes and numbers vary significantly among callers and data resolutions, challenging the definition of an average TAD size, but strengthening the hypothesis that TADs are hierarchically organized domains, rather than disjoint structural elements. Performances of these methods differ based on data resolution and normalization strategy, but a core set of TAD callers consistently retrieve reproducible domains, even at low sequencing depths, that are enriched for TAD-associated biological features.

Conclusions: This study provides a reference for the analysis of chromatin domains from Hi-C experiments and useful guidelines for choosing a suitable approach based on the experimental design, available data, and biological question of interest.
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http://dx.doi.org/10.1186/s13059-018-1596-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6288901PMC
December 2018

Pan-Cancer Landscape of Aberrant DNA Methylation across Human Tumors.

Cell Rep 2018 10;25(4):1066-1080.e8

Department of Computational Biology, University of Lausanne (UNIL), Lausanne, Switzerland; Swiss Institute of Bioinformatics (SIB), University of Lausanne (UNIL), Lausanne, Switzerland. Electronic address:

The discovery of cancer-associated alterations has primarily focused on genetic variants. Nonetheless, altered epigenomes contribute to deregulate transcription and promote oncogenic pathways. Here, we designed an algorithmic approach (RESET) to identify aberrant DNA methylation and associated cis-transcriptional changes across >6,000 human tumors. Tumors exhibiting mutations of chromatin remodeling factors and Wnt signaling displayed DNA methylation instability, characterized by numerous hyper- and hypo-methylated loci. Most silenced and enhanced genes coalesced in specific pathways including apoptosis, DNA repair, and cell metabolism. Cancer-germline antigens (CG) were frequently epigenomically enhanced and their expression correlated with response to anti-PD-1, but not anti-CTLA4, in skin melanoma. Finally, we demonstrated the potential of our approach to explore DNA methylation changes in pediatric tumors, which frequently lack genetic drivers and exhibit epigenomic modifications. Our results provide a pan-cancer map of aberrant DNA methylation to inform functional and therapeutic studies.
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http://dx.doi.org/10.1016/j.celrep.2018.09.082DOI Listing
October 2018

Pan-cancer inference of intra-tumor heterogeneity reveals associations with different forms of genomic instability.

PLoS Genet 2018 09 13;14(9):e1007669. Epub 2018 Sep 13.

Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.

Genomic instability is a major driver of intra-tumor heterogeneity. However, unstable genomes often exhibit different molecular and clinical phenotypes, which are associated with distinct mutational processes. Here, we algorithmically inferred the clonal phylogenies of ~6,000 human tumors from 32 tumor types to explore how intra-tumor heterogeneity depends on different implementations of genomic instability. We found that extremely unstable tumors associated with DNA repair deficiencies or high chromosomal instability are not the most intrinsically heterogeneous. Conversely, intra-tumor heterogeneity is greatest in tumors exhibiting relatively high numbers of both mutations and copy number alterations, a feature often observed in cancers associated with exogenous mutagens. Independently of the type of instability, tumors with high number of clones invariably evolved through branching phylogenies that could be stratified based on the extent of clonal (early) and subclonal (late) instability. Interestingly, tumors with high number of subclonal mutations frequently exhibited chromosomal instability, TP53 mutations, and APOBEC-related mutational signatures. Vice versa, mutations of chromatin remodeling genes often characterized tumors with few subclonal but multiple clonal mutations. Understanding how intra-tumor heterogeneity depends on genomic instability is critical to identify markers predictive of the tumor complexity and envision therapeutic strategies able to exploit this association.
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http://dx.doi.org/10.1371/journal.pgen.1007669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155543PMC
September 2018

Oncogenic Signaling Pathways in The Cancer Genome Atlas.

Cell 2018 04;173(2):321-337.e10

Van Andel Research Institute, 333 Bostwick Ave NE, Grand Rapids Michigan, 49503, USA.

Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.
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http://dx.doi.org/10.1016/j.cell.2018.03.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070353PMC
April 2018

Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas.

Cell Rep 2018 04;23(1):172-180.e3

Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these "hidden responders" may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA) PanCanAtlas project to predict aberrant molecular states in tumors. Applied to the Ras pathway, the method detects Ras activation across cancer types and identifies phenocopying variants. The model, trained on human tumors, can predict response to MEK inhibitors in wild-type Ras cell lines. We also present data that suggest that multiple hits in the Ras pathway confer increased Ras activity. The transcriptome is underused in precision oncology and, combined with machine learning, can aid in the identification of hidden responders.
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http://dx.doi.org/10.1016/j.celrep.2018.03.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918694PMC
April 2018

Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma.

Blood 2018 05 22;131(21):2345-2356. Epub 2018 Mar 22.

Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

In diffuse large B-cell lymphoma (DLBCL), activation of the B-cell receptor (BCR) promotes multiple oncogenic signals, which are essential for tumor proliferation. Inhibition of the Bruton's tyrosine kinase (BTK), a BCR downstream target, is therapeutically effective only in a subgroup of patients with DLBCL. Here, we used lymphoma cells isolated from patients with DLBCL to measure the effects of targeted therapies on BCR signaling and to anticipate response. In lymphomas resistant to BTK inhibition, we show that blocking BTK activity enhanced tumor dependencies from alternative oncogenic signals downstream of the BCR, converging on MYC upregulation. To completely ablate the activity of the BCR, we genetically and pharmacologically repressed the activity of the SRC kinases LYN, FYN, and BLK, which are responsible for the propagation of the BCR signal. Inhibition of these kinases strongly reduced tumor growth in xenografts and cell lines derived from patients with DLBCL independent of their molecular subtype, advancing the possibility to be relevant therapeutic targets in broad and diverse groups of DLBCL patients.
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http://dx.doi.org/10.1182/blood-2017-10-809210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969377PMC
May 2018

Conditional Selection of Genomic Alterations Dictates Cancer Evolution and Oncogenic Dependencies.

Cancer Cell 2017 08 27;32(2):155-168.e6. Epub 2017 Jul 27.

Department of Computational Biology, University of Lausanne (UNIL), 1011 Lausanne, Vaud, Switzerland; Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland. Electronic address:

Cancer evolves through the emergence and selection of molecular alterations. Cancer genome profiling has revealed that specific events are more or less likely to be co-selected, suggesting that the selection of one event depends on the others. However, the nature of these evolutionary dependencies and their impact remain unclear. Here, we designed SELECT, an algorithmic approach to systematically identify evolutionary dependencies from alteration patterns. By analyzing 6,456 genomes from multiple tumor types, we constructed a map of oncogenic dependencies associated with cellular pathways, transcriptional readouts, and therapeutic response. Finally, modeling of cancer evolution shows that alteration dependencies emerge only under conditional selection. These results provide a framework for the design of strategies to predict cancer progression and therapeutic response.
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http://dx.doi.org/10.1016/j.ccell.2017.06.010DOI Listing
August 2017

Genetic and epigenetic inactivation of controls mTORC1 and response to EZH2 inhibition in follicular lymphoma.

Sci Transl Med 2017 06;9(396)

Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Follicular lymphoma (FL) is an incurable form of B cell lymphoma. Genomic studies have cataloged common genetic lesions in FL such as translocation t(14;18), frequent losses of chromosome 6q, and mutations in epigenetic regulators such as Using a focused genetic screen, we identified as a relevant target of the 6q deletion and demonstrate tumor suppression by in vivo. Moreover, is a direct target of the lymphoma-specific gain-of-function mutation ( ). inactivation disrupts p53-mediated control of mammalian target of rapamycin complex 1 (mTORC1) and enables mRNA translation under genotoxic stress. loss represents an alternative to mutations that maintain mTORC1 activity under nutrient starvation. The antitumor efficacy of pharmacological EZH2 inhibition depends on SESTRIN1, indicating that mTORC1 control is a critical function of EZH2 in lymphoma. Conversely, mutant lymphomas show increased sensitivity to RapaLink-1, a bifunctional mTOR inhibitor. Hence, SESTRIN1 contributes to the genetic and epigenetic control of mTORC1 in lymphoma and influences responses to targeted therapies.
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http://dx.doi.org/10.1126/scitranslmed.aak9969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559734PMC
June 2017

The molecular basis of breast cancer pathological phenotypes.

J Pathol 2017 Feb 29;241(3):375-391. Epub 2016 Dec 29.

Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.

The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or reverse-phase protein assay subtype. Marked nuclear pleomorphism, necrosis, inflammation and a high mitotic count were associated with the basal-like subtype, and had a similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed by use of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of poorly differentiated epithelial tubules was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative breast cancer. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has the potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology, and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499709PMC
February 2017

Comprehensive Genetic Landscape of Uveal Melanoma by Whole-Genome Sequencing.

Am J Hum Genet 2016 Nov 13;99(5):1190-1198. Epub 2016 Oct 13.

Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, 1011 Lausanne Switzerland. Electronic address:

Uveal melanoma (UM) is a rare intraocular tumor that, similar to cutaneous melanoma, originates from melanocytes. To gain insights into its genetics, we performed whole-genome sequencing at very deep coverage of tumor-control pairs in 33 samples (24 primary and 9 metastases). Genome-wide, the number of coding mutations was rather low (only 17 variants per tumor on average; range 7-28), thus radically different from cutaneous melanoma, where hundreds of exonic DNA insults are usually detected. Furthermore, no UV light-induced mutational signature was identified. Recurrent coding mutations were found in the known UM drivers GNAQ, GNA11, BAP1, EIF1AX, and SF3B1. Other genes, i.e., TP53BP1, CSMD1, TTC28, DLK2, and KTN1, were also found to harbor somatic mutations in more than one individual, possibly indicating a previously undescribed association with UM pathogenesis. De novo assembly of unmatched reads from non-coding DNA revealed peculiar copy-number variations defining specific UM subtypes, which in turn could be associated with metastatic transformation. Mutational-driven comparison with other tumor types showed that UM is very similar to pediatric tumors, characterized by very few somatic insults and, possibly, important epigenetic changes. Through the analysis of whole-genome sequencing data, our findings shed new light on the molecular genetics of uveal melanoma, delineating it as an atypical tumor of the adult for which somatic events other than mutations in exonic DNA shape its genetic landscape and define its metastatic potential.
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http://dx.doi.org/10.1016/j.ajhg.2016.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097942PMC
November 2016

Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.

Cell 2016 Oct 29;167(2):405-418.e13. Epub 2016 Sep 29.

Cancer Biology & Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas. We report that loss of HVEM leads to cell-autonomous activation of B cell proliferation and drives the development of GC lymphomas in vivo. HVEM-deficient lymphoma B cells also induce a tumor-supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (T) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors. Accordingly, administration of the HVEM ectodomain protein (solHVEM) binds BTLA and restores tumor suppression. To deliver solHVEM to lymphomas in vivo, we engineered CD19-targeted chimeric antigen receptor (CAR) T cells that produce solHVEM locally and continuously. These modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas. Hence, the HVEM-BTLA axis opposes lymphoma development, and our study illustrates the use of CAR-T cells as "micro-pharmacies" able to deliver an anti-cancer protein.
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http://dx.doi.org/10.1016/j.cell.2016.08.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221752PMC
October 2016