Biology subjects

Quatraccioni, A.

Publications and source records attributed to Quatraccioni, A..

3 recordsLinked to original sources

bioRxiv2026

Single-cell profiling reveals tumor grade-dependent immune remodeling in BRAFV600E-driven glioneuronal tumors

BRAFV600E is the key driver variant in epilepsy-associated glioneuronal tumors (GNTs). These tumors often share MAPK/PI3K hyperactivation, a generally benign biological course and rare occurrence of malignant variants. We aimed to characterize the poorly defined immune cell milieu of GNTs with distinct biological behavior. We mapped cellular heterogeneity of the tumor microenvironment (TME) using single-cell transcriptomics on murine models of low-grade (LG-GNT; BRAFV600E/AKTA) and high-grade (HG-GNT; BRAFV600E/AKTA/Trp53KO) tumors, generated via intraventricular in utero electroporation (IUE). Furthermore, ex vivo functional assays with CSF1R-mediated myeloid depletion were utilized to assess the role of identified signaling molecules on tumor viability. We observed a striking, grade-dependent immunological dichotomy: LG-GNT exhibited a permissive niche with prominent surveillance by T cells and pro-inflammatory microglia. In contrast, HG-GNT TME was characterized by a restricted T cell infiltration, massively dominated by myeloid cell infiltrates. Differential gene expression analysis identified Spp1 (osteopontin) as a key mediator of this immunosuppressive HG-GNT TME, exclusively expressed in microglia and border-associated macrophages (BAMs). Crucially, ex vivo functional assays demonstrated that recombinant SPP1 enhances tumor viability through a paracrine mechanism. These findings suggest fundamentally distinct immune activation (a) stimulated by aberrant MAPK/PI3K signaling in LG-GNT, versus (b) malignant tumor feature-driven, e.g. through necrosis in HG-GNT. In the latter, SPP1 signaling creates the immunosuppressive niche. Consequently, while modulating the pro-inflammatory niche may mitigate tumor-related epileptogenicity in LG-GNTs, targeting the SPP1-myeloid axis may restore anti-tumor immunity in HG-GNTs.

neuroscience↗

bioRxiv2021

Heterogeneity and excitability of BRAFV600E-induced tumors is determined by PI3K/mTOR-signaling state and Trp53-loss

BackgroundDevelopmental brain tumors harboring BRAFV600E somatic mutation are diverse. Here, we describe molecular factors that determine BRAFV600E-induced tumor biology and function. MethodsIntraventricular in utero electroporation in combination with the piggyBac transposon system is employed as a tool to generate developmental brain neoplasms. In vivo tumor growth is monitored by using the infrared fluorescent protein (iRFP). Lineage inference is carried out by using the Brainbow transgene. Neural activity from tumor slices is assessed by multielectrode array. RNA sequencing is exploited to analyze the induced neoplasms at the transcriptomic level. ResultsBRAFV600E in murine neural progenitors only in concert with active PI3K/mTOR-signaling through constitutively phosphorylated Akt-kinase (pAkt) elicits benign neoplasms composed of enlarged dysmorphic neurons and neoplastic astroglia recapitulating ganglioglioma (GG). Purely glial tumors partially resembling polymorphous low-grade neuroepithelial tumors of the young (PLNTYs) emerge from BRAFV600E alone. Additional somatic Trp53-loss is sufficient to induce anaplastic GGs (aGGs) with glioneuronal clonality. Functionally, only BRAFV600E/pAkt tumors intrinsically generate substantial neuronal activity and show enhanced relay to adjacent tissue conferring high epilepsy propensity. In contrast, PLNTY- and aGG-models lack significant spike activity, which appears in line with the glial differentiation of the former and a dysfunctional tissue structure combined with reduced neuronal transcript signatures in the latter. ConclusionmTOR-signaling and Trp53-loss critically determine the biological diversity and electrical activity of BRAFV600E-induced tumors. Key pointsO_LIIUE of BRAFV600E and activation of mTOR leads to ganglioglioma (GG)-like tumors, while BRAFV600E alone give rise to PLNTY-like neoplasms. C_LIO_LIAnaplastic GGs depend on the Trp53 deletion in combination to BRAFV600E and PI3K-mTOR signaling cascade. C_LI Importance of the StudyGlioneuronal tumors are challenging with respect to biological behavior and seizure emergence. While BRAFV600E in murine neural precursors induces oligoid tumors, it requires an overactivation of PI3K/mTOR-signaling for the development of hyperexcitable gangliogliomas and additional Trp53-loss for anaplastic transformation.

neuroscience↗

bioRxiv2020

Ste20-like kinase is critical for inhibitory synapse maintenance and its deficiency confers a developmental dendritopathy

The size and structure of the dendritic arbor play important roles in determining how synaptic inputs of neurons are converted to action potential output. The regulatory mechanisms governing the development of dendrites, however, are insufficiently understood. The evolutionary conserved Ste20/Hippo kinase pathway has been proposed to play an important role in regulating the formation and maintenance of dendritic architecture. A key element of this pathway, Ste20-like kinase (SLK), regulates cytoskeletal dynamics in non-neuronal cells and is strongly expressed throughout neuronal development. However, its function in neurons is unknown. We show that during development of mouse cortical neurons, SLK has a surprisingly specific role for proper elaboration of higher, [≥] 3rd, order dendrites. Moreover, we demonstrate that SLK is required to maintain excitation-inhibition balance. Specifically, SLK knockdown caused a selective loss of inhibitory synapses and functional inhibition after postnatal day 15, while excitatory neurotransmission was unaffected. Finally, we show that this mechanism may be relevant for human disease, as dysmorphic neurons within human cortical malformations revealed significant loss of SLK expression. Overall, the present data identify SLK as a key regulator of both dendritic complexity during development and of inhibitory synapse maintenance.

neuroscience↗