I am currently a Postdoctoral research fellow in University of Milan, where I am the leader of several research projects. In March 2022, I have obtained my PhD in Molecular and Cellular biology in Milan. My enthusiasm for pursuing a career in research and development arise from my work in University. In my PhD, I have designed new therapeutic strategies to contrast the development and progression of several tumors, as Glioblastoma and Colorectal cancer.
EDUCATION
March 2022: Ph.D. in Molecular and Cellular Biology. Code: R-11 (English Course), Università degli studi di Milano. Milano, Italy.
Thesis: Transmembrane Chloride Intracellular Channel 1 (tmCLIC1) is key regulator of CRCs’ metastasis
February 2018: Master’s degree in Molecular Biology of the Cell. F9Y, LM-6- Biology class (English Course), Università degli studi di Milano. Milano, Italy
Thesis: A possible role of CLIC1 protein as pharmacological target in solid tumors stem cells.
February 2015: Bachelor’s degree in Scienze Biologiche. L13- Biology class, Università degli studi di Urbino “Carlo Bo”. Urbino, Italy
Thesis: Caratterizzazione di complessi Cu (II)- dendrimeri polilisinici per la biocatalisi
Chronic administration of metformin exerts cytostatic and cytotoxic effects via the PP2A-GSK3β-MCL-1 pathway by inhibiting the tmCLIC1 membrane protein in glioblastoma-initiating cells Francesca Cianci, Ivan Verduci, Riccardo Cazzoli, Gaetano Cannavale, Guido Rey, et al. Journal of Experimental and Clinical Cancer Research, 2025 Background One of the main challenges in cancer treatment is addressing the metabolic reprogramming of tumor cells, which require more energy and biomolecules than healthy cells. Cancer cells alter their metabolism by switching between glycolysis and oxidative phosphorylation (OXPHOS). These processes depend on transmembrane proteins that respond to the extracellular environment. Our research identified the transmembrane form of Chloride Intracellular Channel 1 (tmCLIC1) as a marker of malignancy and a potential therapeutic target. tmCLIC1 levels are increased in several solid tumors, supporting cancer growth and progression, whereas they are mostly absent in healthy cells. We confirmed that tmCLIC1 is the specific target of the antidiabetic drug metformin, an OXPHOS inhibitor in cancer cells. Methods tmCLIC1 is the primary target of metformin in glioblastoma-initiating cells, as shown by single-channel patch-clamp recordings and NMR experiments. Various patient-derived glioblastoma cells with different genetic backgrounds were used to demonstrate that CLIC1 CRISPR-Cas9 knockout and/or its point mutation at arginine 29 removes metformin’s antitumor effects. Functional assays were used to assess the effects on proliferation, mitochondrial metabolism, and tumor growth in vitro and in vivo, using zebrafish and murine xenograft models. Results Metformin inhibits the function of tmCLIC1 through direct and specific binding involving arginine 29 in the tmCLIC1 sequence. Additionally, during hypoglycemia, metformin promotes glioblastoma cell apoptosis by inhibiting the Cancerous Inhibitor of Protein Phosphatase 2 A (CIP2A) and activating the PP2A B56δ subunit. This leads to the dephosphorylation of Glycogen Synthase Kinase 3 Beta (GSK3β), resulting in the breakdown of the pro-survival protein MCL-1 and subsequent cell death. Inhibition of tmCLIC1 is crucial for this metformin-driven antineoplastic effect, mainly through regulating the PP2A-GSK3β-MCL-1 pathway under hypoglycemic conditions. The chronic presence of metformin within the tumors impairs in vivo growth at nanomolar concentrations. Conclusions The therapeutic role of metformin to treat brain tumors remains debated. Our findings show that drug delivery is essential, as in vivo, tumor growth decreases at concentrations below 10 nanomolar. We propose that sustained CNS metformin levels may improve tmCLIC1 inhibition, providing a basis for optimizing interactions with metformin or related compounds to enhance therapeutic efficacy.
Chloride intracellular channel 1 activity is not required for glioblastoma development but its inhibition dictates glioma stem cell responsivity to novel biguanide derivatives Federica Barbieri, Alessia Graziana Bosio, Alessandra Pattarozzi, Michele Tonelli, Adriana Bajetto, et al. Journal of Experimental and Clinical Cancer Research, 2022 Background Chloride intracellular channel-1 (CLIC1) activity controls glioblastoma proliferation. Metformin exerts antitumor effects in glioblastoma stem cells (GSCs) inhibiting CLIC1 activity, but its low potency hampers its translation in clinical settings. Methods We synthesized a small library of novel biguanide-based compounds that were tested as antiproliferative agents for GSCs derived from human glioblastomas, in vitro using 2D and 3D cultures and in vivo in the zebrafish model. Compounds were compared to metformin for both potency and efficacy in the inhibition of GSC proliferation in vitro (MTT, Trypan blue exclusion assays, and EdU labeling) and in vivo (zebrafish model), migration (Boyden chamber assay), invasiveness (Matrigel invasion assay), self-renewal (spherogenesis assay), and CLIC1 activity (electrophysiology recordings), as well as for the absence of off-target toxicity (effects on normal stem cells and toxicity for zebrafish and chick embryos). Results We identified Q48 and Q54 as two novel CLIC1 blockers, characterized by higher antiproliferative potency than metformin in vitro, in both GSC 2D cultures and 3D spheroids. Q48 and Q54 also impaired GSC self-renewal, migration and invasion, and displayed low systemic in vivo toxicity. Q54 reduced in vivo proliferation of GSCs xenotransplanted in zebrafish hindbrain. Target specificity was confirmed by recombinant CLIC1 binding experiments using microscale thermophoresis approach. Finally, we characterized GSCs from GBMs spontaneously expressing low CLIC1 protein, demonstrating their ability to grow in vivo and to retain stem-like phenotype and functional features in vitro. In these GSCs, Q48 and Q54 displayed reduced potency and efficacy as antiproliferative agents as compared to high CLIC1-expressing tumors. However, in 3D cultures, metformin and Q48 (but not Q54) inhibited proliferation, which was dependent on the inhibition dihydrofolate reductase activity. Conclusions These data highlight that, while CLIC1 is dispensable for the development of a subset of glioblastomas, it acts as a booster of proliferation in the majority of these tumors and its functional expression is required for biguanide antitumor class-effects. In particular, the biguanide-based derivatives Q48 and Q54, represent the leads to develop novel compounds endowed with better pharmacological profiles than metformin, to act as CLIC1-blockers for the treatment of CLIC1-expressing glioblastomas, in a precision medicine approach.
Transmembrane chloride intracellular channel 1 (Tmclic1) as a potential biomarker for personalized medicine Francesca Cianci, Ivan Verduci Journal of Personalized Medicine, 2021 Identification of potential pathological biomarkers has proved to be essential for understanding complex and fatal diseases, such as cancer and neurodegenerative diseases. Ion channels are involved in the maintenance of cellular homeostasis. Moreover, loss of function and aberrant expression of ion channels and transporters have been linked to various cancers, and to neurodegeneration. The Chloride Intracellular Channel 1 (CLIC1), CLIC1 is a metamorphic protein belonging to a partially unexplored protein superfamily, the CLICs. In homeostatic conditions, CLIC1 protein is expressed in cells as a cytosolic monomer. In pathological states, CLIC1 is specifically expressed as transmembrane chloride channel. In the following review, we trace the involvement of CLIC1 protein functions in physiological and in pathological conditions and assess its functionally active isoform as a potential target for future therapeutic strategies.
CLIC1 protein accumulates in circulating monocyte membrane during neurodegeneration Valentina Carlini, Ivan Verduci, Francesca Cianci, Gaetano Cannavale, Chiara Fenoglio, et al. International Journal of Molecular Sciences, 2020 Pathologies that lead to neurodegeneration in the central nervous system (CNS) represent a major contemporary medical challenge. Neurodegenerative processes, like those that occur in Alzheimer’s disease (AD) are progressive, and at the moment, they are unstoppable. Not only is an adequate therapy missing but diagnosis is also extremely complicated. The most reliable method is the measurement of beta amyloid and tau peptides concentration in the cerebrospinal fluid (CSF). However, collecting liquid samples from the CNS is an invasive procedure, thus it is not suitable for a large-scale prevention program. Ideally, blood testing is the most manageable and appropriate diagnostic procedure for a massive population screening. Recently, a few candidates, including proteins or microRNAs present in plasma/serum have been identified. The aim of the present work is to propose the chloride intracellular channel 1 (CLIC1) protein as a potential marker of neurodegenerative processes. CLIC1 protein accumulates in peripheral blood mononuclear cells (PBMCs), and increases drastically when the CNS is in a chronic inflammatory state. In AD patients, both immunolocalization and mRNA quantification are able to show the behavior of CLIC1 during a persistent inflammatory state of the CNS. In particular, confocal microscopy analysis and electrophysiological measurements highlight the significant presence of transmembrane CLIC1 (tmCLIC1) in PBMCs from AD patients. Recent investigations suggest that tmCLIC1 has a very specific role. This provides an opportunity to use blood tests and conventional technologies to discriminate between healthy individuals and patients with ongoing neurodegenerative processes.
