Biology subjects

Berico, P.

Publications and source records attributed to Berico, P..

7 recordsLinked to original sources

bioRxiv2026

Chromatin architecture and physical constriction cooperate in phenotype switching and cancer cell dissemination

Phenotypic plasticity is a prominent cancer feature that contributes to metastatic potential and resistance to therapy across multiple cancer types. Cancer cell state transitions have been attributed to transcriptional programs, such as the AP1/TEAD-regulated gene network driving the mesenchymal-like (MES) phenotype. In addition, during dissemination, tumor cells are subjected to variable loads of physical mechanical pressure and constriction across transited tissue, which are thought to impact nuclear molecular crowding. How the interplay between mechanical pressure, global 3D nuclear architecture and transcriptional programs contributes to MES identity and metastatic adaptation remains unclear. Using cutaneous melanoma as a model for early dissemination, we integrate in vitro and in vivo epigenomic profiling with nanoscale imaging of cell lines and patient samples to investigate chromatin organization features underlying the MES phenotype. We find that in MES cells, CTCF is relocated from domain boundaries to regulatory regions of EMT-like genes, leading to reduced insulation, extended topological associated domains (TADs) and increased inter-domain contacts, and de novo formation of chromatin hubs. This conformational rewiring, along with loss of heterochromatin, supports nuclear deformability during invasion and dissemination. Conversely, physical constriction of melanocytic cells induces MES-like chromatin features--including CTCF repositioning and heterochromatin loss-- and promotes metastasis in vivo. Similarly, pharmacological inhibition of the heterochromatin mark H3K9me3 triggers MES characteristics and increases invasiveness. These results demonstrate that metastatic competency involves both epigenetic and structural nuclear reprogramming, enabling shifts in gene networks and physical adaptability. Our findings reveal mechanistic links between nuclear architecture and aggressive tumor behavior, identifying potential biomarkers and therapeutic targets to intercept metastatic progression.

cancer biology↗

bioRxiv2025

The carnosinase dipeptidase CNDP1 is a novel metabolic vulnerability in brain metastasis

Brain metastatic cells undergo metabolic adaptations, such as increased reliance on oxidative phosphorylation. Integrating proteomic and transcriptomic profiling of patient samples revealed a consistent upregulation of the carnosine dipeptidase-1 (CNDP1) in brain versus extracranial metastases. Carnosine is an abundant metabolite in brain and muscle, known to exert anti-proliferative effects on cancer cells. Here, we demonstrate that CNDP1 inhibition suppresses both the establishment and maintenance of melanoma brain metastasis while its ectopic expression is sufficient to confer brain metastatic potential to poorly metastatic cells. CNDP1 suppression results in activation of the Integrated Stress Response via Heme-Regulated Inhibitor Kinase and reprogrammed translation towards preferential expression of mitochondrial and survival transcripts. We further show that CNDP1 upregulation supports mitochondrial activity by limiting the levels of its substrate carnosine, a copper ionophore, thus protecting metastatic cells from carnosine-induced copper toxicity. Our studies reveal a novel metabolic adaptation during brain metastasis, which can be leveraged for therapeutic purposes.

cancer biology↗

bioRxiv2024

A targetable developmental program co-regulates angiogenesis and immune evasion

Ultraviolet (UV)-induced DNA mutations produce genetic drivers of cutaneous melanoma initiation and numerous neoantigens that can trigger anti-tumor immune responses in the host. Consequently, melanoma cells must rapidly evolve to evade immune detection by simultaneously modulating cell-autonomous epigenetic mechanisms and tumor-microenvironment interactions. Angiogenesis has been implicated in this process; although an increase of vasculature initiates the immune response in normal tissue, solid tumors manage to somehow enhance blood flow while preventing immune cell infiltration. By comparing the expression of transcription factors (TFs) across early-stage melanoma, naevi, and other cancer types, we found the homeodomain-containing TF HOXD13 drives a melanoblast-like developmental program, which is upregulated in melanoma and strongly correlated with angiogenesis and immune cell exclusion. Using transcriptomics, 3D chromatin profiling, and in vivo models, we demonstrate that HOXD13 upregulation promotes tumor growth in vivo by concomitantly enhancing angiogenesis and suppressing T-cell infiltration. HOXD13 orchestrates 3D chromatin contacts between distal enhancers and promoters, simultaneously activating VEGFA, SEMA3A, and CD73. VEGFA and SEMA3A remodel the tumor vasculature and CD73 elevates extracellular levels of adenosine, a vasodilator and immune suppressor that binds adenosine receptors (AdR) on endothelial and T cells. In line with these findings, HOXD13-induced growth advantage in vivo was significantly reversed by the concomitant administration of VEGFR and AdR inhibitors. By revealing a dual pro-angiogenic and immunosuppressive HOXD13-CD73/VEGF gene regulatory axis, we identify a subset of patients who might benefit from combinations of AdR and VEGFR inhibitors which are both currently being tested in clinical trials.

cancer biology↗

bioRxiv2024

CRISPR-inhibition screen for lncRNAs linked to melanoma growth and metastasis

Melanoma being one of the most common and deadliest skin cancers, has been rising since the past decade. Patients at advanced stages of the disease have very poor prognoses, as opposed to at the earlier stages. Nowadays the standard-of-care of advanced melanoma is resection followed by immune checkpoint inhibition based immunotherapy. However, a substantial proportion of patients either do not respond or develop resistances. This underscores a need for novel approaches and therapeutic targets as well as a better understanding of the mechanisms of melanoma pathogenesis. Long non-coding RNAs (lncRNAs) comprise a poorly characterized class of functional players and promising targets in promoting malignancy. Certain lncRNAs have been identified to play integral roles in melanoma progression and drug resistances, however systematic screens to uncover novel functional lncRNAs are scarce. Here, we profile differentially expressed lncRNAs in patient derived short-term metastatic cultures and BRAF-MEK-inhibition resistant cells. We conduct a focused growth-related CRISPR-inhibition screen of overexpressed lncRNAs, validate and functionally characterize lncRNA hits with respect to cellular growth, invasive capacities and apoptosis in vitro as well as the transcriptomic impact of our lead candidate the novel lncRNA XLOC_030781. In sum, we extend the current knowledge of ncRNAs and their potential relevance on melanoma. SignificancePreviously considered as transcriptional noise, lncRNAs have emerged as novel players in regulating many cellular aspects in health and disease including melanoma. However, the number and as well as the extent of functional significance of most lncRNAs remains elusive. We provide a comprehensive strategy to identify functionally relevant lncRNAs in melanoma by combining expression profiling with CRISPR-inhibition growths screens lowering the experimental effort. We also provide a larger resource of differentially expressed lncRNAs with potential implications in melanoma growth and invasion. Our results broaden the characterized of lncRNAs as potential targets for future therapeutic applications.

cancer biology↗

bioRxiv2023

Super-enhancer driven expression of BAHCC1 promotes melanomacell proliferation and genome stability

Super enhancers (SE) are stretches of active enhancers ensuring high expression levels of key genes associated with cell function and survival. The identification of cancer-specific SE-driven genes and their functional characterization may prove to be a powerful means for the development of innovative therapeutic strategies. By performing epigenomic profiling in patient-derived short-term melanoma cultures, we identify a SE promoting the specific expression of BAHCC1 in a broad panel of cutaneous and uveal melanoma cells. BAHCC1 is highly expressed in metastatic melanoma, correlates with decreased patient survival and is required for tumor growth. Integrative genomics analyses reveal that BAHCC1 is a transcriptional regulator controlling expression of a subset of E2F/KLF-dependent cell cycle and DNA repair genes. BAHCC1 associates with BRG1-containing remodeling complexes at the promoters of these genes. In agreement, BAHCC1 silencing leads to decreased cell proliferation and delay in DNA repair. Consequently, BAHCC1 deficiency cooperates with PARP inhibition to induce melanoma cell death. Our study identifies a novel SE-driven gene expressed in cutaneous and uveal melanoma and demonstrates how its inhibition can be exploited as a therapeutic target, alone or in combination with DNA damage-inducing agents.

cancer biology↗

bioRxiv2020

TFIIH kinase CDK7 antagonizes phenotype switching and emergence of drug tolerance in melanoma

Melanoma cells switch back-and-forth between phenotypes of proliferation and invasion in response to changing microenvironment, driving metastatic progression. We show that inhibition of the TFIIH kinase CDK7 (CDK7i) results in a melanocytic to mesenchymal phenotype switching and acquisition of targeted therapy tolerance. We identify a gene expression program controlled by the transcription factor GATA6, which participates in drug tolerance in mesenchymal-like cells and which is antagonized by CDK7 in melanocytic-like cells. This program emerges concomitantly with loss of melanocyte lineage-specific MITF protein following CDK7i. By dissecting the underlying mechanism, we observe that CDK7 accumulates at the super-enhancer regulating MITF to drive its expression. MITF itself binds to a intronic region of GATA6 to transcriptionally repress it. This molecular cascade antagonizes expression of the GATA6 regulon that only emerges in MITF-low cells of metastatic melanoma. Our work reveals a role for CDK7 in counteracting phenotype switching and activation of a gene expression program mediating multidrug tolerance in melanoma cells.

cell biology↗

bioRxiv2020

An early Sox2-dependent gene expression program required for hippocampal dentate gyrus development

The hippocampus is a brain area central for cognition. Mutations in the human SOX2 transcription factor cause neurodevelopmental defects, leading to intellectual disability and seizures, together with hippocampal dysplasia. We generated an allelic series of Sox2 conditional mutations in mouse, deleting Sox2 at different developmental stages. Late Sox2 deletion (from E11.5, via Nestin-Cre) affects only postnatal hippocampal development; earlier deletion (from E10.5, Emx1-Cre) significantly reduces the dentate gyrus, and the earliest deletion (from E9.5, FoxG1-Cre) causes drastic abnormalities, with almost complete absence of the dentate gyrus. We identify a set of functionally interconnected genes (Gli3, Wnt3a, Cxcr4, p73 and Tbr2), known to play essential roles in hippocampal embryogenesis, which are downregulated in early Sox2 mutants, and (Gli3 and Cxcr4) directly controlled by SOX2; their downregulation provides plausible molecular mechanisms contributing to the defect. Electrophysiological studies of the Emx1Cre mouse model reveal altered excitatory transmission in CA1 and CA3 regions.

developmental biology↗