Simona Cristea

Simona Cristea
Dana-Farber Cancer Institute | DFCI · Data Science

Doctor of Science

About

47
Publications
6,387
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1,166
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Introduction
I am a Faculty member in Data Sciences at the Dana Farber Cancer Institute and the Head of Data Science at the Hale Center for Pancreatic Cancer. I am also a Research Scientist at the Harvard School of Public Health. My research focuses on developing computational and mathematical models to understand the evolutionary forces driving cancer initiation, progression and invasion. My particular interest is to connect deep learning frameworks with mechanistic descriptions of tumor evolution.

Publications

Publications (47)
Article
The tumor immune microenvironment shapes breast tumor evolution. We previously described the ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) transition as an evolutionary bottleneck and a key step of immune escape. Here, we dissected the cellular composition and spatial topology of DCIS and IBC patient samples and rat tumors that...
Article
Full-text available
Immune escape is a prerequisite for tumor growth. We previously described a decline in intratumor activated cytotoxic T cells and T cell receptor (TCR) clonotype diversity in invasive breast carcinomas compared to ductal carcinoma in situ (DCIS), implying a central role of decreasing T cell responses in tumor progression. To determine potential ass...
Article
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Immune checkpoint blockade (ICB) therapy targeting cytotoxic T-lymphocyte-associated protein 4, programmed death 1, and programmed death ligand 1 has shown durable remission and clinical success across different cancer types. However, patient outcomes vary among disease indications. Studies have identified prognostic biomarkers associated with immu...
Article
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Monocytes and monocyte-derived macrophages (MDM) from blood circulation infiltrate glioblastoma (GBM) and promote growth. Here we show that PDGFB-driven GBM cells induce the expression of the potent pro-inflammatory cytokine IL-1β in MDM, which engages IL-1R1 in tumor cells, activates the NF-kB pathway, and subsequently leads to induction of monocy...
Article
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The epigenetic mechanisms that maintain differentiated cell states remain incompletely understood. Here we employed histone mutants to uncover a crucial role for H3K36 methylation in the maintenance of cell identities across diverse developmental contexts. Focusing on the experimental induction of pluripotency, we show that H3K36M-mediated depletio...
Article
Triple-Negative Breast Cancer (TNBC) is an aggressive breast cancer subset, which lacks expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2. This subset of breast cancer disproportionately affects Black and African American women and improving TNBC treatment options is vital to reducing breast canc...
Article
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Glioblastoma (GBM) is the most aggressive brain tumor, with a median survival of ∼15 months. Targeted approaches have not been successful in this tumor type due to the large extent of intratumor heterogeneity. Mosaic amplification of oncogenes suggests that multiple genetically distinct clones are present in each tumor. To uncover the relationships...
Article
Background Despite the remarkable activity of CDK4/6 inhibitors (CDK4/6i) in the treatment of estrogen receptor positive (ER+) metastatic breast cancer (BC), most patients eventually develop resistance to these drugs. The ctDNA analysis of the PALOMA-3 trial showed that the estrogen receptor (ER) mutation Y537S is a potential mechanism of acquired...
Article
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Cancer prevention has a profound impact on cancer-associated mortality and morbidity. We previously identified TGFβ signaling as a candidate regulator of mammary epithelial cells associated with breast cancer risk. Here, we show that short-term TGFBR inhibitor (TGFBRi) treatment of peripubertal ACI inbred and Sprague Dawley outbred rats induces las...
Preprint
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Monocytes and monocyte-derived macrophages (MDM) from blood circulation infiltrate and promote glioblastoma growth. Here we discover that glioma cells induce the expression of potent pro-inflammatory cytokine IL-1β in MDM, which engages IL-1R1 in glioma cells, activates NF-κB pathway, and subsequently leads to the induction of monocyte chemoattract...
Article
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Heterozygous carriers of germline loss-of-function variants in the tumor suppressor gene checkpoint kinase 2 (CHEK2) are at an increased risk for developing breast and other cancers. While truncating variants in CHEK2 are known to be pathogenic, the interpretation of missense variants of uncertain significance (VUS) is challenging. Consequently, ma...
Article
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Systematic collection of fresh tissues for research at the time of diagnostic image-guided breast biopsy has the potential to fuel a wide variety of innovative studies. Here we report the initial experience, including safety, feasibility, and laboratory proof-of-principle, with the collection and analysis of research specimens obtained via breast c...
Article
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The generation of myotubes from fibroblasts upon forced MyoD expression is a classic example of transcription factor-induced reprogramming. We recently discovered that additional modulation of signaling pathways with small molecules facilitates reprogramming to more primitive induced myogenic progenitor cells (iMPCs). Here, we dissected the transcr...
Article
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Despite the availability of multiple HER2-targeted treatments, therapeutic resistance in HER2+ breast cancer remains a clinical challenge. Intratumor heterogeneity for HER2 and resistance-conferring mutations (e.g., PIK3CA) have been investigated in response and resistance to HER2-targeting agents, while the role of divergent cellular phenotypes an...
Article
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Background: Tumors are widely recognized to progress through clonal evolution by sequentially acquiring selectively advantageous genetic alterations that significantly contribute to tumorigenesis and thus are termned drivers. Some cancer drivers, such as TP53 point mutation or EGFR copy number gain, provide exceptional fitness gains, which, in tim...
Article
Full-text available
Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues of BRCA1 and BRCA2 germline mutation carrier...
Article
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Most human tumours are heterogeneous, composed of cellular clones with different properties present at variable frequencies. Highly heterogeneous tumours have poor clinical outcomes, yet the underlying mechanism remains poorly understood. Here, we show that minor subclones of breast cancer cells expressing IL11 and FIGF (VEGFD) cooperate to promote...
Article
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Cancer extracellular vesicles (EVs) are highly heterogeneous, which impedes our understanding of their function as intercellular communication agents and biomarkers. To deconstruct this heterogeneity, we analyzed extracellular RNAs (exRNAs) and extracellular proteins (exPTNs) from size fractionation of large, medium, and small EVs and ribonucleopro...
Article
Integrating different data types to answer biological questions is a challenging problem, which can, however, provide stronger insights than using each dataset separately. ModulOmics is a statistical framework to integrate multiple omics data types and various statistical tests into one probabilistic model, with the aim of identifying functionally...
Article
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Dissecting cellular differentiation hierarchies in the mammary gland is a prerequisite for understanding both normal development and malignant transformation during tumorigenesis and tumor cell-of-origin. To achieve these goals, several recent papers utilized single cell RNA-seq and lineage tracing to improve our understanding of the composition of...
Article
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Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by extensive intratumoral heterogeneity. To investigate the underlying biology, we conducted single-cell RNA-sequencing (scRNA-seq) of >1500 cells from six primary TNBC. Here, we show that intercellular heterogeneity of gene expression programs within each tumor is variable...
Article
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This month: selected work from the 2018 RECOMB meeting, organized by Ecole Polytechnique and held last April in Paris. This month: selected work from the 2018 RECOMB meeting, organized by Ecole Polytechnique and held last April in Paris.
Preprint
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The identification of molecular pathways driving cancer progression is a fundamental unsolved problem in tumorigenesis, which can substantially further our understanding of cancer mechanisms and inform the development of targeted therapies. Most current approaches to address this problem use primarily somatic mutations, not fully exploiting additio...
Article
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A key feature in the pathogenesis of OSCC is genetic instability, which results in altered expression of genes located in amplified/deleted chromosomal regions. In a previous study we have shown that the amplification of the 11q22.1-q22.2 region, encoding cIAP1 and cIAP2, is associated with lymph node metastasis and poor clinical outcome in OSCC. H...
Article
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We present an integrative genome-wide analysis that can be used to predict the risk of progression from leukoplakia to oral squamous cell carcinoma (OSCC) arising in the gingivobuccal complex (GBC). We find that the genomic and transcriptomic profiles of leukoplakia resemble those observed in later stages of OSCC and that several changes are associ...
Article
Full-text available
We present an integrative genome-wide analysis that can be used to predict the risk of progression from leukoplakia to oral squamous cell carcinoma (OSCC) arising in the gingivobuccal complex (GBC). We find that the genomic and transcriptomic profiles of leukoplakia resemble those observed in later stages of OSCC and that several changes are associ...
Data
Supplementary Table CaptionTable S1: Agilent SureFISH probe details.Table S2: Taqman assay IDs of genes validated by qRT-PCR.Table S3: Antibodies used for immunochemistry (IHC) analysis.Table S4: Literature-based list of genes related to oral cancer.Table S5: Detailed clinicopathological and demographic characteristics of the (A) leukoplakia and (B...
Article
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High-throughput sequencing technologies have facilitated the generation of an unprecedented amount of genomic cancer data, opening the way to a more profound understanding of tumorigenesis. In this endeavor, two fundamental questions have emerged, namely (1) which alterations drive tumor progression and (2) in which order do they occur? Answering t...
Conference Paper
Full-text available
In recent years, high-throughput sequencing technologies have facilitated the generation of an unprecedented amount of genomic cancer data, opening the way to a more profound understanding of tumorigenesis. In this regard, two fundamental questions have emerged: (1) which alterations drive tumor progression? and (2) what are the evolutionary constr...
Article
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The chemoprotective properties of sulforaphane (SF), derived from cruciferous vegetables, are widely acknowledged to arise from its potent induction of xenobiotic-metabolizing and antioxidant enzymes. However, much less is known about the impact of SF on the efficacy of cancer therapy through the modulation of drug-metabolizing enzymes. To identify...
Data
Detailed protocol for SILAC and SF uptake experiments. (DOCX)
Data
Full list of the quantified proteins in the SILAC experiment with their normalized H/L ratio. Column A, B and C: normalized H/L ratios for the three replicate measurements. Column D: Mean of normalized H/L ratios of all three replicate measurements. Column E: Identifiers of proteins contained in the protein group. Column F: Identifiers of proteins...
Data
Full dose-response curve for 48 hours SF treatment in HT29 cells. The calculated IC50 corresponds to 16.7 μM with a 95% confidence interval of 14.3 to 19.6. 2.5 μM correspond to an IC10. (DOCX)
Data
Relative value for quantification of western blots showing levels of AKR1C3 protein in HT29 cells treated with either non-targeting siRNA or siAKR1C3 with or without simultaneous SF treatment (control = 0.1% DMSO). One representative western blot is shown in Fig 3D. Densitometry analysis was done using ImageJ software. Relative expression and 95% c...
Data
Relative value for quantification of western blots showing levels of AKR1C3 protein in seven cell colon cell lines treated with or without 2.5 μM SF for 48 h (control = 0.1% DMSO). One representative western blot is shown in Fig 4B. Densitometry analysis was done using ImageJ software. Relative expression and 95% confidence interval was calculated...
Data
Full coumberone metabolism in all colon cell lines used in this study with (gray) and without (black) SF preconditioning. Bars correspond to mean values and error bars are standard errors. Statistical analysis was performed by an unpaired t-test with Welch’s corrections; **: p < 0.01, *: p < 0.05. (DOCX)
Data
Time course of accumulation of SF in HT29 and HCEC1CT cells. For each assay, cells were exposed to 2.5 or 5 μM SF for specified times at 37°C. At the end of exposure, cells were quickly harvested, separated from medium and lysed, and the content of isothiocyanate in the lysate was measured by cyclocondensation assay (see S1 Appendix). Data is from...
Article
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In contrast to urodele amphibians and teleost fish, mammals lack the regenerative responses to replace large body parts. Amphibian and fish regeneration uses dedifferentiation, i.e., reversal of differentiated state, as a means to produce progenitor cells to eventually replace damaged tissues. Therefore, induced activation of dedifferentiation resp...
Article
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Despite recent technological advances in genomic sciences, our understanding of cancer progression and its driving genetic alterations remains incomplete. We introduce TiMEx, a generative probabilistic model for detecting patterns of various degrees of mutual exclusivity across genetic alterations, which can indicate pathways involved in cancer pro...
Article
Full-text available
Toxicogenomics is an emerging field defined by the adaptation and application of functional genomics techniques to toxicology. Recent advances in generating and analyzing multi-omics data have facilitated the development of toxicogenomics to provide novel answers to many toxicology-related questions. In this chapter, we discuss five recent toxicoge...
Chapter
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Toxicogenomics is an emerging field defined by the adaptation and application of functional genomics techniques to toxicology. Recent advances in generating and analyzing multi-omics data have facilitated the development of toxicogenomics to provide novel answers to many toxicology-related questions. In this chapter, we discuss five recent toxicoge...
Article
Diets enriched with bioactive food components trigger molecular changes in cells that may contribute to either health-promoting or adverse effects. Recent technological advances in high-throughput data generation allow for observing systems-wide molecular responses to cellular perturbations with nontoxic and dietary-relevant doses while considering...
Conference Paper
Large-scale model development for biochemical reaction networks of living cells is currently possible through qualitative model classes such as graphs, Boolean logic, or Petri nets. However, when it is important to understand quantitative dynamic features of a system, uncertainty about the networks often limits large-scale model development. Recent...

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