Biology subjects

Peano, C.

Publications and source records attributed to Peano, C..

9 recordsLinked to original sources

bioRxiv2026

Epigenetic evolution of colorectal cancer and its microenvironment reveals new vulnerabilities

Epigenetics is central to tumorigenesis, but the co-evolution of the cancer epigenome and its microenvironment is severely understudied. Here, we measure chromatin accessibility and transcriptome, at single cell resolution, of a set of normal colon, primary colorectal cancers and metastases, and identify recurrent epigenetic alterations in tumour cells. We also found that the normal epithelium adjacent to the cancer had recurrent epigenetic alterations associated with inflammatory programs that were partially shared with tumour cells. Distinct tumour-intrinsic transcription factor binding programs were associated with differential abundance of malignant stroma cell identities. We then leveraged matched patient-derived organoids, to assess the functional impact of the most recurrent epigenetic alterations on cancer cell viability, using CRISPR interference. We found a set of epigenetic-driven cancer dependencies, related to developmental reprogramming and cellular stress resilience, representing new potential therapeutic targets.

cancer biology↗

bioRxiv2026

Human basal radial glia morphotypes are transcriptionally distinct and exhibit different cell fate determination

Basal radial glia (bRG) are key neural progenitors driving human neocortical expansion. They exhibit remarkable morphological heterogeneity, yet the stability and functional significance of their distinct morphotypes remains unclear. Using human cortical brain organoids combined with long-term live imaging and morphology-resolved spatial transcriptomics (CellShape-seq), we show that bRG morphotypes display distinct morphodynamic behaviors, proliferative capacities and transcriptional profiles. While bifurcated bRG remodel extensively during mitosis to produce morphologically diverse progeny, multipolar cells are most morphologically flexible during interphase. Multipolar bRG further show the greatest proliferative capacity and the transcriptional signature related to progenitor state. Bifurcated bRG are least proliferative and are enriched for the multifunctional gene expression regulator YBX1. Pharmacological inhibition of YBX1 depletes bifurcated bRG, reduces neurogenesis, and promotes glial commitment. Our findings link progenitor morphology, gene expression and fate, providing a framework for understanding the cellular logic of human cortical development.

neuroscience↗

bioRxiv2025

Competing gene regulatory networks drive naive and memory B cell differentiation

Elucidating the gene regulatory networks (GRNs) that govern human B cell differentiation is essential for understanding immune responses to infection, vaccination and autoantigens. Here, we show that individual naive B cells can give rise to both plasma cells and germinal centre (GC) B cells. In contrast, memory B cells display a progressive increase in IRF4 activity over time, leading to PRDM1 induction and exclusive differentiation into plasma cells. Using CRISPR-based perturbations, we demonstrate that IRF4 is indispensable for both GC and plasma cell development. Notably, IRF4 promotes GC fate independently of PRDM1, as PRDM1 disruption did not impair GC differentiation. We also find that while the abundance of antibody mRNAs is clonally correlated, class switch recombination (CSR) occurs stochastically and is clonally independent. Together, these findings reveal distinct regulatory dynamics during naive and memory B cell activation and offer new insights into the GRNs underlying human B cell fate decisions.

immunology↗

bioRxiv2025

Glioblastoma stem cell morphotypes convey distinct cell states and clinically relevant functions

Glioblastoma (GBM) is an aggressive brain tumor and an unmet clinical need due to its invasiveness and therapy-resistance. These features are driven by glioblastoma stem cells (GSCs), which exhibit remarkable functional heterogeneity. However, GSC transcriptional profiling alone cannot predict clinically relevant behaviors. Here, we developed CellShape-seq, a spatial transcriptomics platform that integrates cell morphology with transcriptome. This identified three GSC morphoclasses corresponding to distinct transcriptomic states and functions: (1) nonpolar cells show differentiation and therapy sensitivity, (2) elongated cells are invasive, and (3) multipolar cells form intercellular networks. Importantly, chemoresistance is morphoclass-specific: elongated GSCs depend on YAP/TEAD1 signaling, while multipolar GSCs rely on gap junction-mediated networks. Targeting these vulnerabilities with specific inhibitors sensitized resistant GSC morphoclasses to temozolomide (TMZ) in patient-derived organoids. Our findings demonstrate that morphology provides critical insights into GSC behavior and establish a rationale for morphology-informed therapies to overcome resistance and improve outcomes in GBM. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/644884v2_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@141e698org.highwire.dtl.DTLVardef@18a238corg.highwire.dtl.DTLVardef@23ef62org.highwire.dtl.DTLVardef@1390c07_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Targeted Antisense Oligonucleotide Treatment Rescues Developmental Alterations in Spinal Muscular Atrophy Organoids

Spinal muscular atrophy (SMA) is a severe neurological disease caused by mutations in the SMN1 gene, characterized by early onset and degeneration of lower motor neurons. Understanding early neurodevelopmental defects in SMA is crucial for optimizing therapeutic interventions. Using spinal cord and cerebral organoids generated from multiple SMA type I donors, we revealed widespread disease mechanisms beyond motor neuron degeneration. Single-cell transcriptomics uncovered pervasive alterations across neural populations, from progenitors to neurons, demonstrating SMN-dependent dysregulation of neuronal differentiation programs. Multi-electrode array analysis identified consistent hyperexcitability in both spinal and brain organoids, establishing altered electrical properties as a central nervous system-wide feature of pathogenesis. Early administration of an optimized antisense oligonucleotide (ASO) that restored SMN levels rescued morphological and functional deficits in spinal cord organoids across different genetic backgrounds. Importantly, this early intervention precisely corrected aberrant splicing in newly identified SMN1 targets enriched at critical nodes of neuronal differentiation. Our findings demonstrate that early developmental defects are core features of SMA pathogenesis that can be prevented by timely therapeutic intervention, providing new insights for optimizing treatment strategies.

neuroscience↗

bioRxiv2023

Human iPSC-derived neural stem cells display a radial glia-like signature in vitro and favorable long-term safety in transplanted mice

Human induced pluripotent stem cell-derived neural stem/progenitor cells (hiPSC-NSCs) are a promising source for cell therapy approaches to treat neurodegenerative and demyelinating disorders. Despite ongoing efforts to characterize hiPSC-derived cells in vitro and in vivo, we lack comprehensive genome- and transcriptome-wide studies addressing hiPSC-NSC identity and safety, which are critical for establishing accepted criteria for prospective clinical applications. Here, we evaluated the transcriptional and epigenetic signatures of hiPSCs and differentiated hiPSC-NSC progeny, finding that the hiPSC-to-NSC transition results in a complete loss of pluripotency and the acquisition of a radial glia-associated transcriptional signature. Importantly, hiPSC-NSCs share with somatic human fetal NSCs (hfNSCs) the main transcriptional and epigenetic patterns associated with NSC-specific biology. In vivo, long-term observation (up to 10 months) of mice intracerebrally transplanted as neonates with hiPSC-NSCs showed robust engraftment and widespread distribution of human cells in the host brain parenchyma. Engrafted hiPSC-NSCs displayed multilineage potential and preferentially generated glial cells. No hyperproliferation, tumor formation, or expression of pluripotency markers was observed. Finally, we identified a novel role of the Sterol Regulatory Element Binding Transcription Factor 1 (SREBF1) in the regulation of astroglial commitment of hiPSC-NSCs. Overall, these comprehensive in vitro and in vivo analyses provide transcriptional and epigenetic reference datasets to define the maturation stage of NSCs derived from different hiPSC sources, and to clarify the safety profile of hiPSC-NSCs, supporting their continuing development as an alternative to somatic hfNSCs in treating neurodegenerative and demyelinating disorders.

neuroscience↗

bioRxiv2022

Multimodal single-cell profiling of intrahepatic cholangiocarcinoma defineshyperactivated Tregs as a potential therapeutic target

The quality of the immune infiltrate of intrahepatic cholangiocarcinoma (iCCA), a rare, yet aggressive tumor of the biliary tract, remains poorly characterized, limiting development of successful immunotherapies. We used high-dimensional flow cytometry to characterise the T cell and myeloid compartments of iCCA comparing these with their tumor-free peritumoral and circulating counterparts. We found poor infiltration of putative tumor-specific CD39+ CD8+ T cells accompanied by abundant infiltration of hyperactivated CD4+ regulatory T cells (Tregs), whose frequency in relation to that of CD4+ CD69+ T cells and conventional type 2 dendritic cells was associated with poor prognosis. Single-cell RNA-sequencing identified an altered network of transcription factors in iCCA-infiltrating compared to peritumoral T cells, suggesting reduced effector functions by tumor-infiltrating CD8+ T cells and enhanced immunosuppression by CD4+ Tregs. Specifically, we found that expression of mesenchyme homeobox 1 (MEOX1) was highly enriched in tumor-infiltrating Tregs, and demonstrated that MEOX1 overexpression is sufficient to reprogram circulating precursors to acquire the transcriptional and epigenetic landscape of tumorinfiltrating Tregs. Interfering with hyperactivated Tregs should be thus explored to enhance antitumor immunity in iCCA.

immunology↗

bioRxiv2020

Mutated clones driving leukemic transformation are already detectable at the single cell level in CD34-positive cells in the chronic phase of primary myelofibrosis

Disease progression of myeloproliferative neoplasms is the result of increased genomic complexity. Since the ability to predict disease evolution is crucial for clinical decision, we studied single cell genomics and transcriptomics of CD34-positive cells from a primary myelofibrosis (PMF) patient who progressed to acute myeloid Leukemia (AML) while receiving Ruxolitinib. Single cell genomics allowed the reconstruction of clonal hierarchy and demonstrated that TET2 was the first mutated gene while FLT3 was the last one. Disease evolution was accompanied by increased clonal heterogeneity and mutational rate, but clones carrying TP53 and FLT3 mutations were already present in chronic phase. Single cell transcriptomics unraveled repression of interferon signaling suggesting an immunosuppressive effect exerted by Ruxolitinib. Moreover, AML transformation was associated with a differentiative block and immune escape. These results suggest that single cell analysis can unmask tumor heterogeneity and provide meaningful insights about PMF progression that might guide personalized therapy.

cancer biology↗

bioRxiv2020

Transient Maternal IL-6 boosts glutamatergic synapses and disrupts hippocampal connectivity in the offspring

Early prenatal inflammatory conditions are thought to represent a risk factor for different neurodevelopmental disorders, with long-term consequences on adult brain connectivity. Here we show that a transient IL-6 elevation, occurring at vulnerable stages of early neurodevelopment, directly impacts brain developmental trajectories through the aberrant enhancement of glutamatergic synapses and overall brain hyper-connectivity. The IL6-mediated boost of excitatory synapse density results from the neuron-autonomous, genomic effect of the transcription factor STAT3 and causally involves the activation of RGS4 gene as a candidate downstream target. The STAT3/RGS4 pathway is also activated in neonatal brains as a consequence of maternal immune activation protocols mimicking a viral infection during pregnancy. By demonstrating that prenatal IL-6 elevations result in aberrant synaptic and brain connectivity through the molecular players identified, we provide a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders.

neuroscience↗