Biology subjects

Arrigoni, C.

Publications and source records attributed to Arrigoni, C..

5 recordsLinked to original sources

bioRxiv2025

A High-Throughput Bone Marrow 3D Co-Culture System to Develop Resistance to B Cell Receptor Signaling Targeted Agents in B Cell Non-Hodgkin Lymphoma

B cell receptor (BCR) signaling plays a central role in the pathogenesis of B cell lymphomas, making it a crucial therapeutic target. The advent of BCR-targeted inhibitors, particularly those directed at PI3K and BTK, has revolutionized treatment for B cell non-Hodgkin lymphoma (B-NHL). However, therapeutic resistance remains a significant clinical challenge. Increasing evidence suggests that the tumor microenvironment (TME), particularly the bone marrow (BM) microenvironment, is crucial in driving cancer progression and therapeutic resistance. The BM microenvironment provides a specialized niche where lymphoma cells can evade therapy through interactions with stromal cells and extracellular matrix (ECM) components. Bone marrow stromal cells (BMSCs) contribute significantly to this resistance. In this study, we developed an in vitro 3D model to better understand B cell lymphoma biology and drug resistance mechanisms. We co-cultured lymphoma cell lines with primary BMSCs in a 3D fibrin gel matrix using a high-throughput and automated system. Our results revealed that BMSCs modulate lymphoma cell growth and reduce their sensitivity to the PI3K inhibitor copanlisib and the BTK inhibitor ibrutinib. Furthermore, this model allowed us to identify IGFBP-3, Serpin E1, and PTX-3 as potential mediators of therapeutic resistance. These findings underscore the value of using 3D co-culture models in preclinical settings to more accurately study drug resistance, as they more closely simulate the BM microenvironments complexity than traditional 2D models, thus improving the predictive value of drug testing in B cell lymphomas. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/632958v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@72bc6aorg.highwire.dtl.DTLVardef@afdda2org.highwire.dtl.DTLVardef@1fff494org.highwire.dtl.DTLVardef@11252cf_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOVisual AbstractC_FLOATNO C_FIG

cancer biology↗

bioRxiv2023

VDAC1 selective molecules promote patients-derived cancer organoids death through mitochondrial-dependent metabolic interference

In the continuous pursuit of advanced cancer therapeutics, our research unveils the potential to selectively target Voltage-Dependent Anion-selective Channel isoform 1 (VDAC1), a pivotal component in cellular metabolism and apoptosis. VDAC1s role in metabolic rewiring and its subsequent prominence in many cancer types offer a unique intervention point. The incorporation of a systematic, in silico to in vitro methodology identified novel VA (VDAC-Antagonist) molecules with the capability to selectively bind to VDAC1, displaying a substantial specificity towards cancer cells while sparing healthy ones. This research first led to the revelation of a specialized VDAC1 pocket, which accommodates the binding of these VA molecules, thereby instigating a selective displacement of NADH. The coenzyme is a critical metabolic substrate, and its displacement ensues in notable mitochondrial distress and a reduction in cell proliferation, specifically in cancer cells. Furthermore, meticulous analysis using organoids derived from intrahepatic cholangiocarcinoma patients (iCCA) demonstrated a dose-dependent reduction in cell viability upon treatment with VA molecules, correlating with the findings from commercial cell lines. Interestingly, VA molecules significantly reduced cell viability and demonstrated a lower impact on healthy cells than conventional treatments like gemcitabine. This differential impact is possibly due to the elevated expression of VDAC1 in various cancer cell lines, rendering them more susceptible to metabolic disruptions induced by VA molecules. This endeavor uncovers a multifaceted approach to cancer treatment, involving meticulous targeting of metabolic gatekeepers like VDAC1 using novel entities, thereby paving the way for developing more selective and refined cancer therapeutics. The identified VA molecules, albeit in the nascent stages, represent promising candidates for further optimization and development, potentially revolutionizing treatment modalities in cancer therapy through precise metabolic interventions.

biophysics↗

bioRxiv2021

Quaternary structure independent folding of voltage-gated ion channel pore domain subunits

Every voltage-gated ion channel (VGIC) superfamily member has an ion conducting pore consisting of four pore domain (PD) subunits that are each built from a common plan comprising an antiparallel transmembrane helix pair, a short, obliquely positioned helix (the pore helix), and selectivity filter. The extent to which this structure, the VGIC-PD fold, relies on the extensive quaternary interactions observed in PD assemblies is unclear. Here, we present crystal structures of three bacterial voltage-gated sodium channel (BacNaO_SCPLOWVC_SCPLOW) pores that adopt a surprising set of non-canonical quaternary structures and yet maintain the native tertiary structure of the PD monomer. This context-independent structural robustness demonstrates that the VGIC-PD fold, the fundamental VGIC structural building block, can adopt its native-like tertiary fold independent of native quaternary interactions. In line with this observation, we find that the VGIC-PD fold is not only present throughout the VGIC superfamily and other channel classes but has homologs in diverse transmembrane and soluble proteins. Characterization of the structures of two synthetic Fabs (sFabs) that recognize the VGIC-PD fold shows that such sFabs can bind purified full-length channels and indicates that non-canonical quaternary PD assemblies can occur in the context of complete VGICs. Together, our data demonstrate that the VGIC-PD structure can fold independently of higher-order assembly interactions and suggest that full-length VGIC PDs can access previously unknown non-canonical quaternary states. These PD properties have deep implications for understanding how the complex quaternary architectures of VGIC superfamily members are achieved and point to possible evolutionary origins of this fundamental VGIC structural element.

biophysics↗

bioRxiv2021

Systems biology analysis identifies TCF7L1 as a key regulator of metastasis in Ewing sarcoma

Identification of cancer stemness genes is crucial to understanding the underlying biology of therapy resistance, relapse, and metastasis. Ewing sarcoma (EwS) is the second most common bone tumor in children and adolescents. It is a highly aggressive cancer associated with a dismal survival rate (<30%) for patients with metastatic disease at diagnosis ([~]25% of cases). Hence, deciphering the underlying mechanisms of metastasis is imperative. EwS tumors are characterized by a remarkably silent genome with a single driver mutation generating an oncogenic fusion transcription factor (EWSR1-ETS). Thus, EwS constitutes an ideal model to study how perturbation of a transcriptional network by a dominant oncogene can mediate metastasis, even though canonical metastasis-associated genes are not mutated. Here, through the implementation of an integrative systems biology approach, we identified transcription factor 7 like 1 (TCF7L1, alias TCF3) as a prognostically-relevant and EWSR1-ETS suppressed determinant of metastasis in EwS. We demonstrated that conditional TCF7L1 re-expression significantly reduces EwS single-cell migration, invasion and anchorage-independent growth in 3D assays in vitro, and tumorigenesis in vivo mediated by its DNA binding domain. In primary EwS tumors as well as in functional orthotopic in vivo models, low TCF7L1 expression was associated with pro-metastatic gene signatures and a much higher migratory and metastatic capacity of EwS cells, which correlated with poor outcome of EwS patients. Collectively, our findings establish TCF7L1 as a major regulator of metastasis in EwS, which may be utilized as a prognostic biomarker and open inroads to future therapeutic intervention.

cancer biology↗

bioRxiv2019

Oncogenic hijacking of a developmental transcription factor evokes therapeutic vulnerability for ROS-induction in Ewing sarcoma

Ewing sarcoma (EwS) is an aggressive childhood cancer likely originating from mesenchymal stem cells or osteo-chondrogenic progenitors. It is characterized by fusion oncoproteins involving EWSR1 and variable members of the ETS-family of transcription factors (in 85% FLI1). EWSR1-FLI1 can induce target genes by using GGAA-microsatellites (mSats) as enhancers.\n\nHere, we show that EWSR1-FLI1 hijacks the developmental transcription factor SOX6 - a physiological driver of proliferation of osteo-chondrogenic progenitors - by binding to an intronic GGAA-mSat, which promotes EwS growth in vitro and in vivo. Through integration of transcriptome-profiling, published drug-screening data, and functional in vitro and in vivo experiments, we discovered that SOX6 interferes with the antioxidant system resulting in constitutively elevated reactive oxygen species (ROS) levels that create a therapeutic vulnerability toward the ROS-inducing drug Elesclomol.\n\nCollectively, our results exemplify how aberrant activation of a developmental transcription factor by a dominant oncogene can promote malignancy, but provide opportunities for targeted therapy.

cancer biology↗