Biology subjects

Avalle, L.

Publications and source records attributed to Avalle, L..

6 recordsLinked to original sources

bioRxiv2026

Psychedelic Hormesis: LSD Activates Adaptive Stress Transcriptional Programs in the Prefrontal Cortex

Background Classic psychedelics are serotonergic agents increasingly recognized for their ability to produce rapid and long-lasting therapeutic effects in several neuropsychiatric conditions, yet the molecular mechanisms that translate acute serotonergic perturbation into long-term brain adaptation remain poorly understood. Psychedelic action is commonly attributed to enhanced neuronal plasticity, but emerging evidence suggests broader engagement of stress-responsive and homeostatic processes across neural and non-neural cell types. Methods To define the temporal structure of psychedelic-induced transcriptional responses, we profiled gene expression in the prefrontal cortex of mice at early and delayed time points following a single administration of lysergic acid diethylamide (LSD). Differentially expressed genes were then contextualized through pathway-level and cross-dataset comparisons with established models of adaptive and chronic stress. Results LSD induced a coherent, temporally organized transcriptional program extending beyond immediate neuronal activation. Early responses reflected adaptive metabolic and stress-related signaling, whereas later ones involved circadian and neuroendocrine regulation. A persistent transcriptional core spanning both time points indicated sustained regulation of metabolic, circadian, and stress-responsive pathways. Comparative analyses showed that, although LSD-induced transcriptional profile shares features with general stress responses, its preferentially aligns with adaptive, hormetic stress paradigms rather than maladaptive chronic stress. Conclusions These findings indicate that in the prefrontal cortex LSD activates adaptive stress transcriptional programs consistent with hormetic adaptation, providing a molecular framework to interpret the enduring effects of psychedelics beyond synaptic plasticity.

molecular biology↗

bioRxiv2026

Lysergic acid diethylamide reverses aging- and neurodegeneration-associated brain transcriptional programs

Psychedelic compounds such as lysergic acid diethylamide (LSD) are increasingly studied for their neuroplastic effects and potential relevance to brain aging and neurodegeneration. However, the molecular mechanisms linking psychedelic-induced plasticity to age-associated cognitive decline remain unclear. Brain aging and dementia are characterized by coordinated transcriptional programs that underlie synaptic dysfunction and altered neuron-glia interactions. If psychedelic-induced plasticity engages opposing molecular programs, it could counteract these conserved trajectories. In computational drug discovery, this concept has been formalized as the principle of transcriptional signature reversal, whereby compounds inducing gene expression states opposite to disease-associated programs may exert a therapeutic effect by counteracting disease-associated phenotypes. Here, we combine cross-species transcriptomic analyses with experimental validation to test whether LSD opposes conserved signatures of brain aging and dementia. By comparing transcriptional profiles induced by chronic LSD treatment in rodents with age- and dementia-associated gene expression changes in the human prefrontal cortex, we show that LSD induces gene expression patterns strongly anti-correlated with aging and neurodegeneration programs. This reversal is specific compared to other pharmacological perturbations and is reproducible across datasets and species. Moreover, LSD counteracts amyloid-{beta}-induced structural and molecular alterations in primary cortical neurons, linking transcriptomic opposition to functional rescue under neurodegenerative stress. Together, our findings suggest that LSD modulates molecular and cellular pathways associated with brain aging and neurodegeneration, linking systems-level gene expression changes to structural and functional resilience in neurodegeneration-relevant contexts.

neuroscience↗

bioRxiv2025

Lactate Blocks Tertiary Lymphoid Structure Formation by Inhibiting B Cell Chemotaxis

Tertiary lymphoid structures (TLS) and B cell infiltration are strong predictors of immunotherapy success across cancers, including triple-negative breast cancer (TNBC). However, immune-cold TNBCs often lack both features. Here, we identify a tumor-intrinsic mechanism that actively suppresses B cell recruitment. Despite evidence of B cell responses in cancer-associated lymph nodes (cLNs), B cells fail to infiltrate TNBC tumors or form TLS. This exclusion is not simply due to chemokine deficiency as exogenous chemokine addition fails to restore B cell migration. Using fractionation and metabolic profiling, we identify lactate as a dominant tumor-secreted metabolite that directly impairs B cell chemotaxis by disrupting mitochondrial metabolism. In vivo, combining lactate inhibition with engineered chemokine secretion promotes cLN-derived B cell infiltration and enables TLS formation, particularly when coupled with CD40 stimulation. Transcriptomics analyses across several human cancer datasets strengthen the association between high glycolytic activity with poor B-cell infiltration in chemokine-rich tumors. Together, our findings reveal lactate as a key metabolic barrier to B cell trafficking and TLS induction, suggesting that metabolic reprogramming may provide an avenue to convert "immune-cold" tumors into TLS-rich, immunologically responsive microenvironments.

cancer biology↗

bioRxiv2023

A novel ILK/STAT3 pathway controls plasticity in a neural stem cell model of glioblastoma.

Glioblastomas (GBM) are driven by malignant neural stem-like cells that display extensive heterogeneity and phenotypic plasticity, which drives tumour progression and therapeutic resistance. Here we show that the nodal extracellular matrix-cell adhesion protein integrin-linked kinase (ILK; a pseudokinase), is a key determinant of phenotypic plasticity and the mesenchymal-like, invasive cell state in mouse GBM stem cells. We found that a novel ILK-STAT3 signalling pathway is required for plasticity that enables the transition of GBM stem cells to an astrocyte-like state both in vitro and in vivo. GBM cells genetically depleted of ILK become predominantly stabilised in a transcriptionally-defined progenitor-like state that is characterised by lack of response to differentiation cues and constitutive proliferation. Loss of ILK or interference with STAT3 impairs differentiation potential, reducing phenotypic plasticity of tumour cell populations; additionally, ILK loss causes a mesenchymal- to epithelial-like morphological transition and suppression of malignancy-associated features. Our work defines ILK as a central regulator of multiple GBM phenotypes including phenotypic plasticity and mesenchymal state.

cancer biology↗

bioRxiv2019

Network analysis allows to unravel breast cancer molecular features and to identify novel targets

The behaviour of complex biological systems is determined by the orchestrated activity of many components interacting with each other, and can be investigated by networks. In particular, gene co-expression networks have been widely used in the past years thanks to the increasing availability of huge gene expression databases. Breast cancer is a heterogeneous disease usually classified either according to immunohistochemical features or by expression profiling, which identifies the 5 subtypes luminal A, luminal B, basal-like, HER2-positive and normal-like. Basal-like tumours are the most aggressive subtype, for which so far no targeted therapy is available.\n\nMaking use of the WGCNA clustering method to reconstruct breast cancer transcriptional networks from the METABRIC breast cancer dataset, we developed a platform to address specific questions related to breast cancer biology. In particular, we obtained gene modules significantly correlated with survival and age of onset, useful to understand how molecular features and gene expression patterns are organized in breast cancer. We next generated subtype-specific gene networks and in particular identified two modules that are significantly more connected in basal-like breast cancer with respect to all other subtypes, suggesting relevant biological functions. We demonstrate that network centrality (kWithin) is a suitable measure to identify relevant genes, since we could show that it correlates with clinical features and that it provides a mean to select potential upstream regulators of a module with high reliability. Finally, we showed the feasibility of adding meaning to the networks by combining them with independently obtained data related to activated pathways.\n\nIn conclusion, our platform allows to identify groups of genes highly relevant in breast cancer and possibly amenable to drug targeting, due to their ability to regulate survival-related gene networks. This approach could be successfully extended to other BC subtypes, and to all tumor types for which enough expression data are available.

cancer biology↗

bioRxiv2018

SP1 and STAT3 functionally synergize to induce the RhoU small GTPase and a subclass of non-canonical WNT responsive genes correlating with poor prognosis in breast cancer.

Breast cancer is a complex disease in which heterogeneity makes clinical management very challenging. Although breast cancer subtypes classified according to specific molecular features are associated to better or worse prognosis, the identification of specific markers predicting disease outcome within the single subtypes still lags behind. Both the non-canonical WNT and the STAT3 pathways are often constitutively activated in breast tumors, and both can induce the small GTPase RhoU gene transcription. Here we show that RhoU transcription can be triggered by both canonical and non-canonical WNT ligands via the activation of JNK and the recruitment of the SP1 transcription factor to the RhoU promoter, identifying for the first time SP1 as a JNK-dependent mediator of WNT signaling. RhoU down-regulation by silencing or treatment with JNK, SP1 or STAT3 inhibitors lead to impaired cell migration in basal-like MDA-MB-231 cells, which display constitutive activation of both the non-canonical WNT and STAT3 pathways. These data suggest that STAT3 and SP1 can cooperate to induce high RhoU expression and enhance migration of breast cancer cells. In vivo binding of both factors characterizes a group of SP1/STAT3 responsive genes belonging to the non-canonical WNT and the IL-6/STAT3 pathways. High expression of this signature is significantly correlated with poor prognosis across all profiled patients. Thus, concomitant binding of both STAT3 and SP1 defines a subclass of genes contributing to breast cancer aggressiveness, suggesting the relevance of developing novel targeted therapies combining inhibitors of the STAT3 and WNT pathways or of their downstream mediators.\n\nNovelty and ImpactThe WNT and STAT3 pathways are often activated in breast tumors, but whether they can cooperate towards aggressiveness is not presently known. Here the authors show that WNT ligands can elicit the activation of the transcription factor SP1, which cooperates with STAT3 to induce a subset of non-canonical WNT and IL-6/STAT3 genes. Expression of this gene signature correlates with bad prognosis in breast cancer, suggesting coordinated interference with both TFs as a novel therapeutic option.

cancer biology↗