Single-Nuclei Transcriptome Profiling Reveals Intra-Tumoral Heterogeneity and Characterizes Tumor Microenvironment Architecture in a Murine Melanoma Model.

Malignant melanoma is an aggressive cancer, with a high risk of metastasis and mortality rates, characterized by cancer cell heterogeneity and complex tumor microenvironment (TME). Single cell biology is an ideal and powerful tool to address these features at a molecular level. However, this approach requires enzymatic cell dissociation that can influence cellular coverage.

XENTURION is a population-level multidimensional resource of xenografts and tumoroids from metastatic colorectal cancer patients.

The breadth and depth at which cancer models are interrogated contribute to the successful clinical translation of drug discovery efforts. In colorectal cancer (CRC), model availability is limited by a dearth of large-scale collections of patient-derived xenografts (PDXs) and paired tumoroids from metastatic disease, where experimental therapies are typically tested. Here we introduce XENTURION, an open-science resource offering a platform of 128 PDX models from patients with metastatic CRC, along with matched PDX-derived tumoroids.

Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer.

Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5 stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1 stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease.

Phosphoproteomics of patient-derived xenografts identifies targets and markers associated with sensitivity and resistance to EGFR blockade in colorectal cancer.

Epidermal growth factor receptor (EGFR) is a well-exploited therapeutic target in metastatic colorectal cancer (mCRC). Unfortunately, not all patients benefit from current EGFR inhibitors. Mass spectrometry-based proteomics and phosphoproteomics were performed on 30 genomically and pharmacologically characterized mCRC patient-derived xenografts (PDXs) to investigate the molecular basis of response to EGFR blockade and identify alternative drug targets to overcome resistance.

Multi-label transcriptional classification of colorectal cancer reflects tumor cell population heterogeneity.

Background: Transcriptional classification has been used to stratify colorectal cancer (CRC) into molecular subtypes with distinct biological and clinical features. However, it is not clear whether such subtypes represent discrete, mutually exclusive entities or molecular/phenotypic states with potential overlap. Therefore, we focused on the CRC Intrinsic Subtype (CRIS) classifier and evaluated whether assigning multiple CRIS subtypes to the same sample provides additional clinically and biologically relevant information.

CONNECTOR, fitting and clustering of longitudinal data to reveal a new risk stratification system.

Motivation: The transition from evaluating a single time point to examining the entire dynamic evolution of a system is possible only in the presence of the proper framework. The strong variability of dynamic evolution makes the definition of an explanatory procedure for data fitting and clustering challenging.

Results: We developed CONNECTOR, a data-driven framework able to analyze and inspect longitudinal data in a straightforward and revealing way.

EGAsubmitter: A software to automate submission of nucleic acid sequencing data to the European Genome-phenome Archive.

Making raw data available to the research community is one of the pillars of Findability, Accessibility, Interoperability, and Reuse (FAIR) research. However, the submission of raw data to public databases still involves many manually operated procedures that are intrinsically time-consuming and error-prone, which raises potential reliability issues for both the data themselves and the ensuing metadata. For example, submitting sequencing data to the European Genome-phenome Archive (EGA) is estimated to take 1 month overall, and mainly relies on a web interface for metadata management that requires manual completion of forms and the upload of several comma separated values (CSV) files, which are not structured from a formal point of view.

Colorectal cancer patient-derived organoids and cell lines harboring ATRX and/or DAXX mutations lack Alternative Lengthening of Telomeres (ALT).

Telomere maintenance is necessary to maintain cancer cell unlimited viability. However, the mechanisms maintaining telomere length in colorectal cancer (CRC) have not been extensively investigated. Telomere maintenance mechanisms (TMM) include the re-expression of telomerase or alternative lengthening of telomeres (ALT).

Synthetic Lethal Interaction with BCL-XL Blockade Deepens Response to Cetuximab in Patient-Derived Models of Metastatic Colorectal Cancer.

Purpose: Approximately 20% of patients with RAS wild-type metastatic colorectal cancer (mCRC) experience objective responses to the anti-EGFR antibody cetuximab, but disease eradication is seldom achieved. The extent of tumor shrinkage correlates with long-term outcome. We aimed to find rational combinations that potentiate cetuximab efficacy by disrupting adaptive dependencies on antiapoptotic molecules (BCL2, BCL-XL, MCL1).

Becoming a mother during the COVID-19 pandemic: The lived experience as told by birthing mothers: A qualitative study.

Aims And Objectives: The aim of this study is to explore the lived experience of women who gave birth during the COVID-19 pandemic.

Background: Experiencing pregnancy during the Covid-19 pandemic exacerbates the risk of the onset of psychological problems.

Design: This is a descriptive, single-centre, qualitative study.

Towards precision oncology with patient-derived xenografts.

Under the selective pressure of therapy, tumours dynamically evolve multiple adaptive mechanisms that make static interrogation of genomic alterations insufficient to guide treatment decisions. Clinical research does not enable the assessment of how various regulatory circuits in tumours are affected by therapeutic insults over time and space. Likewise, testing different precision oncology approaches informed by composite and ever-changing molecular information is hard to achieve in patients.

Measurement invariance of the Liebowitz Social Anxiety Scale-Self-Report.

Objective: The Liebowitz Social Anxiety Scale-Self Report (LSAS-SR) is a self-report measure of social anxiety (SA), which has shown adequate psychometric properties across cultures. However, no study has systematically evaluated its measurement invariance (MI) between (a) individuals with and without a diagnosis of social anxiety disorder (SAD) and (b) males and females. The current study addresses this issue.

Chromatin Velocity reveals epigenetic dynamics by single-cell profiling of heterochromatin and euchromatin.

Recent efforts have succeeded in surveying open chromatin at the single-cell level, but high-throughput, single-cell assessment of heterochromatin and its underlying genomic determinants remains challenging. We engineered a hybrid transposase including the chromodomain (CD) of the heterochromatin protein-1α (HP-1α), which is involved in heterochromatin assembly and maintenance through its binding to trimethylation of the lysine 9 on histone 3 (H3K9me3), and developed a single-cell method, single-cell genome and epigenome by transposases sequencing (scGET-seq), that, unlike single-cell assay for transposase-accessible chromatin with sequencing (scATAC-seq), comprehensively probes both open and closed chromatin and concomitantly records the underlying genomic sequences. We tested scGET-seq in cancer-derived organoids and human-derived xenograft (PDX) models and identified genetic events and plasticity-driven mechanisms contributing to cancer drug resistance.

PhyliCS: a Python library to explore scCNA data and quantify spatial tumor heterogeneity.

Background: Tumors are composed by a number of cancer cell subpopulations (subclones), characterized by a distinguishable set of mutations. This phenomenon, known as intra-tumor heterogeneity (ITH), may be studied using Copy Number Aberrations (CNAs). Nowadays ITH can be assessed at the highest possible resolution using single-cell DNA (scDNA) sequencing technology.

ESDN inhibits melanoma progression by blocking E-selectin expression in endothelial cells via STAT3.

An interactive crosstalk between tumor and stroma cells is essential for metastatic melanoma progression. We evidenced that ESDN/DCBLD2/CLCP1 plays a crucial role in endothelial cells during the spread of melanoma. Precisely, increased extravasation and metastasis formation were revealed in ESDN-null mice injected with melanoma cells, even if the primary tumor growth, vessel permeability, and angiogenesis were not enhanced.

Pertuzumab and trastuzumab emtansine in patients with HER2-amplified metastatic colorectal cancer: the phase II HERACLES-B trial.

Background: HER2 is a therapeutic target for metastatic colorectal cancer (mCRC), as demonstrated in the pivotal HERACLES-A (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification) trial with trastuzumab and lapatinib. The aim of HERACLES-B trial is to assess the efficacy of the combination of pertuzumab and trastuzumab-emtansine (T-DM1) in this setting.

Methods: HERACLES-B was a single-arm, phase II trial, in patients with histologically confirmed wild-type and HER2+ mCRC refractory to standard treatments.

Colorectal cancer residual disease at maximal response to EGFR blockade displays a druggable Paneth cell-like phenotype.

Blockade of epidermal growth factor receptor (EGFR) causes tumor regression in some patients with metastatic colorectal cancer (mCRC). However, residual disease reservoirs typically remain even after maximal response to therapy, leading to relapse. Using patient-derived xenografts (PDXs), we observed that mCRC cells surviving EGFR inhibition exhibited gene expression patterns similar to those of a quiescent subpopulation of normal intestinal secretory precursors with Paneth cell characteristics.

eQTL Mapping Using Transcription Factor Affinity.

In the last decades, thousands of common genetic variants have been associated with human diseases by genome-wide association studies (GWAS). However, the functional interpretation of GWAS hits is usually nontrivial, especially because most of them lay outside the coding genome. These noncoding variants presumably exert their effect by altering gene expression levels; therefore, expression quantitative trait loci (eQTL) mapping analyses represent an important step in understanding their functional relevance and identifying the target genes.

Immunogenomics of Colorectal Tumors: Facts and Hypotheses on an Evolving Saga.

Immunotherapy with immune checkpoint inhibitors is an approved treatment option for a subpopulation of patients with colorectal cancers that display microsatellite instability. However, not all individuals within this subgroup respond to immunotherapy, and molecular biomarkers for effective patient stratification are still lacking. In this opinion article, we provide an overview of the different biological parameters that contribute to rendering colorectal cancers with microsatellite instability potentially sensitive to immunotherapy.

The Length of the Expressed 3' UTR Is an Intermediate Molecular Phenotype Linking Genetic Variants to Complex Diseases.

In the last decades, genome-wide association studies (GWAS) have uncovered tens of thousands of associations between common genetic variants and complex diseases. However, these statistical associations can rarely be interpreted functionally and mechanistically. As the majority of the disease-associated variants are located far from coding sequences, even the relevant gene is often unclear.

Choice of Alternative Polyadenylation Sites, Mediated by the RNA-Binding Protein Elavl3, Plays a Role in Differentiation of Inhibitory Neuronal Progenitors.

Alternative polyadenylation (APA) is a widespread mechanism involving about half of the expressed genes, resulting in varying lengths of the 3' untranslated region (3'UTR). Variations in length and sequence of the 3'UTR may underlie changes of post-transcriptional processing, localization, miRNA targeting and stability of mRNAs. During embryonic development a large array of mRNAs exhibit APA, with a prevalence of the longer 3'UTR versions in differentiating cells.

Evolutionary Rewiring of Human Regulatory Networks by Waves of Genome Expansion.

Genome expansion is believed to be an important driver of the evolution of gene regulation. To investigate the role of a newly arising sequence in rewiring regulatory networks, we estimated the age of each region of the human genome by applying maximum parsimony to genome-wide alignments with 100 vertebrates. We then studied the age distribution of several types of functional regions, with a focus on regulatory elements.