Francesca Demichelis

Francesca Demichelis
Università degli Studi di Trento | UNITN · CIBIO - Centre for Integrative Biology

Professor

About

387
Publications
41,385
Reads
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28,901
Citations
Additional affiliations
January 2018 - present
Università degli Studi di Trento
Position
  • Professor
January 2011 - December 2017
Università degli Studi di Trento
Position
  • Leader in Computational Oncology
October 2007 - June 2011
Weill Cornell Medical College
Position
  • Research Assistant

Publications

Publications (387)
Article
Gene fusions of the AR-regulated gene TMPRSS2 with the ETS family transcription factor ERG characterize about 40% of castration resistant prostate cancer (CRPC) - an advanced and lethal stage of prostate cancer. AR-mediated overexpression of ERG hijacks AR inhibiting lineage-specific differentiation and increases cell invasion and migration. In viv...
Article
Sequencing of cell-free DNA (cfDNA) in cancer patients' plasma offers a minimally-invasive solution to detect tumor cell genomic alterations to aid real-time clinical decision-making. The reliability of copy number detection decreases at lower cfDNA tumor fractions, limiting utility at earlier stages of the disease. To test a novel strategy for det...
Preprint
Bladder Cancer (BLCa) inter-patient heterogeneity is considered the primary cause of tumor reoccurrence and treatment failure, suggesting that BLCa patients could benefit from a more personalized treatment approach. Patient-derived organoids (PDOs) have been successfully used as a functional model for predicting drug response in different cancer ty...
Article
Full-text available
21q22.2–3 deletion is the most common copy number alteration in prostate cancer (PCa). The genomic rearrangement results in the androgen-dependent de novo expression of ETS-related gene (ERG) in prostate cancer cells, a condition promoting tumor progression to advanced stages of the disease. Interestingly, ERG expression characterizes 5–30% of tumo...
Article
Full-text available
The ETS family member ERG is a transcription factor with physiological roles during development and in the vascular and hematopoietic systems. ERG oncogenic activity characterizes several malignancies, including Ewing’s sarcoma, leukemia and prostate cancer (PCa). In PCa, ERG rearrangements with androgen-regulated genes—mostly TMPRSS2—characterize...
Article
Primary prostate cancer (PCa) can show marked molecular heterogeneity. However, systematic analyses comparing primary PCa and matched metastases in individual patients are lacking. We aimed to address the molecular aspects of metastatic progression while accounting for heterogeneity of primary PCa. In this pilot study, we collected 12 radical prost...
Article
Full-text available
Differentially DNA methylated regions (DMRs) inform on the role of epigenetic changes in cancer. We present Rocker-meth, a new computational method exploiting a heterogeneous hidden Markov model to detect DMRs across multiple experimental platforms. Through an extensive comparative study, we first demonstrate Rocker-meth excellent performance on sy...
Article
Full-text available
Pan-cancer studies sketched the genomic landscape of the tumor types spectrum. We delineated the purity- and ploidy-adjusted allele-specific profiles of 4,950 patients across 27 tumor types from the Cancer Genome Atlas (TCGA). Leveraging allele-specific data, we reclassified as loss of heterozygosity (LOH) 9% and 7% of apparent copy-number wild-typ...
Article
Full-text available
Cancer is a risk factor for venous thromboembolism (VTE). Plasma tumor DNA (ptDNA) is an independent predictor of outcome in metastatic castration-resistant prostate cancer (mCRPC). We aimed to investigate the association between ptDNA and VTE in mCRPC. This prospective biomarker study included 180 mCRPC patients treated with abiraterone and enzalu...
Article
Growing bodies of evidence have demonstrated that the identification of prostate cancer (PCa) biomarkers in the patients’ blood and urine may remarkably improve PCa diagnosis and progression monitoring. Among diverse cancer–derived circulating materials, extracellular RNA molecules (exRNAs) represent a compelling component to investigate cancer-rel...
Article
Full-text available
Mutual Exclusivity analysis of genomic aberrations contributes to the exploration of potential synthetic lethal (SL) relationships thus guiding the nomination of specific cancer cells vulnerabilities. When multiple classes of genomic aberrations and large cohorts of patients are interrogated, exhaustive genome-wide analyses are not computationally...
Article
5048 Background: Cancer is a risk factor for VTE. In mCRPC, ptDNA is an independent predictor of outcome ( Romanel, Sci Transl Med 2015; Conteduca, Br J Cancer 2020). We firstly aimed to investigate the association between ptDNA and VTE in mCRPC men treated with androgen receptor signaling inhibitors (ARSI) Methods: This prospective biomarker study...
Article
BACKGROUND Molecular characterization of prostate cancer (PCa) has revealed distinct subclasses based on underlying genomic alterations occurring early in the natural history of the disease. However, how these early alterations influence subsequent molecular events and the course of the disease over its long natural history remains unclear.METHODS...
Article
Full-text available
Background CD38, a druggable ectoenzyme, is involved in the generation of adenosine, which is implicated in tumour immune evasion. Its expression and role in prostate tumour-infiltrating immune cells (TIICs) have not been elucidated. Objective To characterise CD38 expression on prostate cancer (PC) epithelial cells and TIICs, and to associate this...
Article
141 Background: Recently, plasma tumour DNA (ptDNA) has been identified as a potential early noninvasive biomarker of treatment response in mCRPC patients ( Conteduca, Br J Cancer 2020). In this study, we sought to determine whether pre-treatment ptDNA could accurately reflect metabolic tumor burden in mCRPC and if it could be in combination with f...
Article
An Erratum to this paper has been published: https://doi.org/10.1038/s41576-020-00313-9.
Article
Intratumour heterogeneity and phenotypic plasticity, sustained by a range of somatic aberrations, as well as epigenetic and metabolic adaptations, are the principal mechanisms that enable cancers to resist treatment and survive under environmental stress. A comprehensive picture of the interplay between different somatic aberrations, from point mut...
Article
Full-text available
Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in around 10–20% of these patients is lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we invest...
Preprint
Full-text available
Differentially DNA methylated regions (DMRs) inform on the role of epigenetic changes in cancer. We present Rocker-meth, a computational method exploiting a heterogeneous hidden Markov model to detect DMRs across multiple experimental platforms. Its application to more than 6,000 methylation profiles across 14 tumor types provides a comprehensive c...
Article
Purpose: The tumor microenvironment is complex, comprising heterogeneous cellular populations. As molecular profiles are frequently generated using bulk tissue sections, they represent an admixture of multiple cell types (including immune, stromal, and cancer cells) interacting with each other. Therefore, these molecular profiles are confounded by...
Article
Plasma tumour DNA (ptDNA) levels on treatment are associated with response in a variety of cancers. However, the role of ptDNA in prostate cancer monitoring remains largely unexplored. Here we characterised on-treatment ptDNA dynamics and evaluated its potential for early assessment of therapy efficacy for metastatic castration-resistant prostate c...
Article
Full-text available
Background The link between inflammation and cancer development was intensively studied in the last decade. To date, few studies explored the association between inflammatory genes and colorectal cancer (CRC) development. Aim The present study aimed to evaluate the implication of three single nucleotide polymorphisms (SNPs), rs28362491 ins/del −94...
Article
Full-text available
Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is among the most common diseases affecting aging men, but the underlying molecular features remain poorly understood, and therapeutic options are limited. Here we employ a comprehensive molecular investigation of BPH, including genomic, transcriptomic and epigenetic pr...
Article
Full-text available
Tumor DNA circulates in the plasma of cancer patients admixed with DNA from noncancerous cells. The genomic landscape of plasma DNA has been characterized in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome has not been extensively explored. Here, we performed next-generation sequencing (NGS) on plasma DNA with and w...
Preprint
Full-text available
Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in ~10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investi...
Article
Full-text available
Loss of androgen receptor (AR) signaling dependence occurs in approximately 15%-20% of advanced treatment-resistant prostate cancers, and this may manifest clinically as transformation from a prostate adenocarcinoma histology to a castration-resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE currently relies on a metastati...
Article
8 Background: Loss of androgen receptor signaling dependence occurs in approximately 20% of treatment resistant prostate cancers, and this may manifest as transformation to castration resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE relies on a metastatic tumor biopsy, which is invasive for patients. Here we study ctDNA...
Article
Motivation: The use of liquid biopsies for cancer patients enables the non-invasive tracking of treatment response and tumor dynamics through single or serial blood drawn tests. Next generation sequencing assays allow for the simultaneous interrogation of extended sets of somatic single nucleotide variants (SNVs) in circulating cell free DNA (cfDN...
Article
Full-text available
Background: Interrogation of whole exome and targeted sequencing NGS data is rapidly becoming a preferred approach for the exploration of large cohorts in the research setting and importantly in the context of precision medicine. Single-base and genomic region level data retrieval and processing still constitute major bottlenecks in NGS data analy...
Conference Paper
Loss of androgen receptor (AR) signaling dependence occurs in approximately 15-20% of treatment resistant prostate cancers, and this may manifest clinically as transformation from a prostate adenocarcinoma histology to a castration resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE currently relies on a metastatic tumor bi...
Article
Background Tumour DNA circulates in the plasma of cancer patients admixed with DNA from non-cancerous cells. The genomic landscape of plasma tumour DNA has been characterised in metastatic castration-resistant prostate cancer (mCRPC) but the plasma methylome in mCRPC has not been extensively explored. Methods mCRPC plasma samples collected from th...
Preprint
Full-text available
Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is one of the most common diseases affecting aging men, but the underlying molecular features of BPH remain poorly understood, and therapeutic options are limited. Here we employed a comprehensive molecular investigation of BPH, including genomic, transcriptomic and epi...
Article
Full-text available
High‐throughput DNA sequencing technology provides base‐level and statistically rich information about the genomic content of a sample. In the contexts of cancer research and precision oncology, thousands of genomes from paired tumor and matched normal samples are profiled and processed to determine somatic copy‐number changes and single‐nucleotide...
Article
Full-text available
Purpose: We developed a precision medicine program for patients with advanced cancer using integrative whole-exome sequencing and transcriptome analysis. Patients and methods: Five hundred fifteen patients with locally advanced/metastatic solid tumors were prospectively enrolled, and paired tumor/normal sequencing was performed. Seven hundred fi...
Article
Full-text available
Repetitive sequences are hotspots of evolution at multiple levels. However, due to difficulties involved in their assembly and analysis, the role of repeats in tumor evolution is poorly understood. We developed a rigorous motif-based methodology to quantify variations in the repeat content, beyond microsatellites, in proteomes and genomes directly...
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Conference Paper
DNA methylation (DNAm) is an essential player of gene regulation and therefore one of the most studied epigenetic mechanisms. Alterations of DNAm have been associated with a wide range of diseases, including cancer. Most studies on DNAm focused on the characterization of methylation sites, despite the recognition that DNAm changes spanning entire g...
Article
5039 Background: Plasma ctDNA is a promising minimally invasive biomarker in mCRPC. Pre-treatment high levels of ctDNA reflect poor prognosis (Romanel et al, Sci Transl Med 2015; Annala et al, Cancer Discov 2018). However, the role of plasma ctDNA in prostate tumour monitoring is largely unexplored. We aimed to determine if monitoring tumour respon...
Article
Full-text available
Motivation: Tumor purity (TP) is the proportion of cancer cells in a tumor sample. TP impacts on the accurate assessment of molecular and genomics features as assayed with NGS approaches. State-of-the-art tools mainly rely on somatic copy-number alterations (SCNA) to quantify TP and therefore fail when a tumor genome is nearly euploid, i.e. "non-a...
Article
Full-text available
Heterogeneity in the genomic landscape of metastatic prostate cancer has become apparent through several comprehensive profiling efforts, but little is known about the impact of this heterogeneity on clinical outcome. Here, we report comprehensive genomic and transcriptomic analysis of 429 patients with metastatic castration-resistant prostate canc...
Article
Full-text available
Background: Extracellular vesicles (EVs) are secreted membranous particles intensively studied for their potential cargo of diagnostic markers. Efficient and cost-effective isolation methods need to be established for the reproducible and high-throughput study of EVs in the clinical practice. Methods: We designed the nickel-based isolation (NBI)...
Article
Full-text available
The clinical behavior of prostate cancer is highly heterogeneous, with most patients diagnosed with localized disease that successfully responds to surgery or radiotherapy or that can be followed by active surveillance. However, a fraction of men will relapse after initial treatment and eventually progress to an aggressive resistant form with metas...
Preprint
Full-text available
Repetitive sequences are hotspots of evolution at multiple levels. However, due to technical difficulties involved in their assembly and analysis, the role of repeats in tumor evolution is poorly understood. We developed a rigorous motif-based methodology to quantify variations in the repeat content of proteomes and genomes, directly from proteomic...
Poster
Full-text available
Prostate cancer is a clinically and genetically heterogeneous disease and despite the big advances over the years for the management of the disease, molecular targets and biomarkers still need to be identified for more effective patients' treatment and stratification. Large sequencing efforts (e.g. The Cancer Genome Atlas (TCGA), Stand Up to Cancer...
Article
Full-text available
Purpose: Metastatic castration resistant prostate cancer (mCRPC) is a lethal but clinically heterogeneous disease, with patients having variable benefit from endocrine and cytotoxic treatments. Intra-patient genomic heterogeneity could be a contributing factor to this clinical heterogeneity. Here we used whole-genome sequencing (WGS) to investigat...
Article
Background: Neuroendocrine prostate cancer (NEPC) is an aggressive variant of prostate cancer that may develop de novo or as a mechanism of treatment resistance. N-myc is capable of driving NEPC progression. Alisertib inhibits the interaction between N-myc and its stabilizing factor Aurora-A, inhibiting N-myc signaling, and suppressing tumor growt...
Poster
The Cancer Genome Atlas (TCGA) characterizes the landscape of the somatic copy number aberrations (SCNA) of multiple tumor types and provides for each gene a measure proportional to the number of DNA copies. However, tumor purity and cancer cell ploidy affect the estimation of SCNA and may lead to incorrect interpretations of gene status. We presen...
Article
Full-text available
Background Genomic characterization of prostate cancer (PCa) biopsies may improve criteria for the selection of patients suitable for active surveillance (AS). Objective To identify somatic genomic aberrations associated with adverse outcome as AS protocol exclusion indicators. Design, setting and participants Whole-exome sequencing profiles were...
Article
Prostate cancer (PCa) is the most commonly diagnosed cancer and the third highest cause of cancer-related death in men in Europe, where it is responsible for over 90,000 deaths a year. The mainstay of treatment for metastatic PCa is androgen-deprivation therapy (ADT). Although initially effective, the treatment ultimately fails and progression to c...