Biology subjects

Corleone, G.

Publications and source records attributed to Corleone, G..

4 recordsLinked to original sources

bioRxiv2022

Enhancer plasticity sustains oncogenic transformation and progression of B-Cell Acute Lymphoblastic leukemia.

Growing evidence report that non-genetic-driven events such as enhancer reprogramming promote neoplastic transformation and strongly contribute to the phenotypical heterogeneity of cancers as much as genetic variation. In this context, we investigated the role of enhancers in sustaining oncogenic transformation in B-Cell Acute Lymphoblastic leukemia in children (BCP-ALL), a type of cancer caused by the accumulation of lymphoid progenitor cells in the bone marrow and a leading cause of cancer-related mortality in children. Using next-generation sequencing (ATAC-seq), we built the most up-to-date map of chromatin accessibility in pediatric BCP-ALL. We observed that enhancer activity dynamically changes during cancer progression and represents principal phenomena underlying phenotypic-functional characteristics of BCP-ALL progression. BCP-ALL patients are dominated by a regulatory repertoire (N=[~]11k) originally represented at diagnosis that shrinks under treatments and subsequently re-expands, driving the relapse. We then deployed a wide range of in-vivo, in-vitro assays, and in-silico analyses to demonstrate the impact of enhancer activity in determining the phenotypical complexity. CRISPR-Cas-9-mediated validation of selected productive enhancers demonstrated a high capability of these regions to control MYB and DCTD oncogenic activities. Taken together, these findings provide direct support to the notion that enhancer plasticity is a crucial determinant of the BCP-ALL phenotype.

cancer biology↗

bioRxiv2021

AATF/Che-1, a new component of paraspeckles, controls R-loops formation and Interferon activation in Multiple Myeloma.

Multiple myeloma (MM) is a hematological neoplasm of plasma cells characterized by abnormal production of immunoglobulins. Che-1/AATF (Che-1) is an RNA binding protein involved in transcription regulation and is highly expressed in this malignancy. Here we experimentally show that Che-1 interacts with paraspeckle components, including the lncRNA NEAT1_2 (NEAT1), which serves as the seed for the maintenance of these structures. Che-1 and NEAT1 localize on R-loops, three-stranded RNA:DNA hybrids structures involved in DNA transcription and repair. Depletion of Che-1 produces a marked accumulation of RNA:DNA hybrids sustaining activation of a systemic inflammatory response. We provide evidence that high levels of Unfolded Protein Response (UPR) in MM cells induces RNA:DNA hybrids and an interferon (IFN) gene signature. We found that MM patients exhibit elevated R-loops levels and paraspeckle genes mRNAs increase linearly to MM progression. Strikingly, patients showing elevated IFN genes signature are associated with a marked poor prognosis. Overall, these findings delineate that elevated R-loops accumulation and inflammatory signaling may contribute to MM progression and that Che-1/NEAT1 plays an essential role in maintaining R-loops homeostasis by preventing excessive inflammatory signaling.

cell biology↗

bioRxiv2018

Single-cell Transcriptomics reveals multi-step adaptations to endocrine therapy

Resistant tumours are thought to arise from the action of Darwinian selection on genetically heterogenous cancer cell populations. However, simple clonal selection is inadequate to describe the late relapses often characterising luminal breast cancers treated with endocrine therapy (ET), suggesting a more complex interplay between genetic and non-genetic factors. Partially, this is due to our limited understanding on the effect of ET at the single cell level. In the present study, we dissect the contributions of clonal genetic diversity and transcriptional plasticity during the early and late phases of ET at single-cell resolution. Using single-cell RNA-sequencing and imaging we disentangle the transcriptional variability of plastic cells and define a rare sub-population of pre-adapted (PA) cells which undergoes further transcriptomic reprogramming and copy number changes to acquire full resistance. PA cells show reduced oestrogen receptor activity but increased features of quiescence and migration. We find evidence for sub-clonal expression of this PA signature in primary tumours and for dominant expression in clustered circulating tumour cells. We propose a multi-step model for ET resistance development and advocate the use of stage-specific biomarkers.

cancer biology↗

bioRxiv2017

Enhancers mapping uncovers phenotypic heterogeneity and evolution in patients with luminal breast cancer.

The degree of intrinsic and interpatient phenotypic heterogeneity and its role in tumour evolution is poorly understood. Phenotypic divergence can be achieved via the inheritance of alternative transcriptional programs1,2. Cell-type specific transcription is maintained through the activation of epigenetically-defined regulatory regions including promoters and enhancers1,3,4. In this work, we annotated the epigenome of 47 primary and metastatic oestrogen-receptor (ER)-positive breast cancer specimens from clinical samples, and developed strategies to deduce phenotypic heterogeneity from the regulatory landscape, identifying key regulatory elements commonly shared across patients. Highly shared regions contain a unique set of regulatory information including the motif for the transcription factor YY1. In vitro work shows that YY1 is essential for ER transcriptional activity and defines the critical subset of functional ER binding sites driving tumor growth in most luminal patients. YY1 also control the expression of genes that mediate resistance to endocrine treatment. Finally, we show that H3K27ac levels at active enhancer elements can be used as a surrogate of intra-tumor phenotypic heterogeneity, and to track expansion and contraction of phenotypic subpopulations throughout breast cancer progression. Tracking YY1 and SLC9A3R1 positive clones in primary and metastatic lesions, we show that endocrine therapies drive the expansion of phenotypic clones originally underrepresented at diagnosis. Collectively, our data show that epigenetic mechanisms significantly contribute to phenotypic heterogeneity and evolution in systemically treated breast cancer patients.

cancer biology↗