Biology subjects

Tosoni, D.

Publications and source records attributed to Tosoni, D..

4 recordsLinked to original sources

bioRxiv2026

p140Cap enhances breast cancer chemosensitivity by limiting an ABCC1-enriched stem-like compartment via β-Catenin inhibition

Chemotherapy response in breast cancer is highly heterogeneous and influenced by tumor-intrinsic drivers of drug sensitivity, including cancer stem cell abundance. We previously reported that the scaffold protein p140Cap limits breast cancer stem cell traits and delays tumor progression. Here, we investigated the role of p140Cap in shaping sensitivity to chemotherapy in HER2-positive and triple-negative breast cancer. In preclinical and patient-derived models, p140Cap enhances chemotherapy response by increasing intracellular doxorubicin retention, DNA damage and subsequent apoptosis. Mechanistically, p140Cap constrained a doxorubicin-negative side population enriched for stem-like properties and elevated ABCC1 expression via inhibition of {beta}-Catenin signaling. Constitutively active {beta}-Catenin expression reversed this phenotype, whereas pharmacological inhibition of the Wnt/{beta}-Catenin pathway with IWR-1 or LGK-974 sensitized p140Cap-deficient tumors to chemotherapy. Clinically, analyses of breast cancer cohorts and patient-derived xenograft models identify p140Cap as predictive biomarker of chemotherapy response, proposing p140Cap-guided patient stratification, dose optimization and rational combination therapies.

cancer biology↗

bioRxiv2025

The CRL7FBXW8 Complex Controls the Mammary Stem Cell Compartment Through Regulation of NUMB Levels

NUMB is a tumor suppressor gene that functions by inhibiting the action of the NOTCH proto-oncogene and enhancing the levels and activity of the tumor suppressor protein p53. In breast cancer (BC), NUMB loss-of-function (LOF), mediated by various molecular mechanisms, is a frequent and causal event. Herein, we establish that loss of NUMB protein, resulting from protein hyper-degradation, is the prevalent mechanism of NUMB LOF in BC. Through a RNAi-based screening, we identified the CRL7FBXW8 complex as the E3 ligase complex responsible for NUMB hyper-degradation in BC. Genetic and pharmacological inhibition of CRL7FBXW8 rescued the transformation-related phenotypes induced by NUMB LOF in BC cell lines and in patient-derived xenografts. These effects were directly dependent on the restoration of NUMB protein levels. Thus, enhanced CRL7FBXW8 activity, through its interference with the tumor suppressor activity of NUMB, is a causal alteration in BC, suggesting it as a potential therapeutic target for precision medicine.

cancer biology↗

bioRxiv2024

Loss of the tumor suppressor NUMB drives aggressive bladder cancer through hyperactivation of a RhoA/ROCK/YAP signaling circuitry

Bladder cancer (BCa) is one of the most challenging and costly cancers to treat, yet little progress has been made on the development of predictive biomarkers and targeted therapies. Here, we uncover a critical function of Numb as a tumor suppressor in the bladder, identifying loss of Numb expression as a causal alteration in BCa that underlies biological aggressiveness and disease progression. Through retrospective cohort studies, we established that a Numb-deficient tumor status correlates with worse overall survival in post-cystectomy muscle-invasive bladder cancer (MIBC) patients and increased risk of MIBC progression in non-muscle-invasive bladder cancer (NMIBC) patients. The prognostic value of Numb loss can be attributed to its crucial role as a determinant of aggressive bladder tumorigenesis, as demonstrated in mouse and human models. Targeted Numb ablation in the basal layer of the urothelium was alone sufficient to trigger spontaneous bladder tumorigenesis and drive progression from preneoplastic to preinvasive and, ultimately, overtly invasive tumors. Additionally, Numb ablation sensitized the urothelium to other oncogenic insults, accelerating tumor onset and progression. Using 3D-Matrigel organoid cultures to recapitulate bladder tumorigenesis in vitro, we found that Numb loss heightens the proliferative and invasive potential of both mouse and human BCa cells. Integrative transcriptomic and functional analyses revealed that downregulation of the canonical Hippo pathway, resulting in enhanced YAP transcriptional activity, underlies the biological aggressiveness of Numb-deficient BCa. These molecular events are dependent on the activation of RhoA/ROCK signaling subsequent to Numb loss. Thus, a dysfunctional Numb-RhoA/ROCK-Hippo/YAP regulatory network is at play in aggressive Numb-deficient BCa and represents a therapeutic vulnerability. A 27-gene prognostic signature capable of identifying high-risk Numb-deficient patients could provide the basis of a clinical tool to stratify patients for innovative RhoA/ROCK/YAP targeted therapies. One Sentence SummaryNumb loss-directed hyperactivation of RhoA/ROCK/YAP underlies aggressive bladder cancer biology.

cancer biology↗

bioRxiv2023

A novel, RAS-independent role for NF1 in microtubular dynamics and damage repair dictates sensitivity to T-DM1 in HER2-positive breast cancer

Antibody-Drug Conjugates (ADC) have revolutionized the treatment of several tumors, and extensive research is being devoted to the identification of predictive biomarkers. These are particularly sought after in fields, like breast cancer, in which multiple ADCs with identical target but different payloads have been approved. NF1 is a tumor suppressor widely mutated across several cancers, best characterized as an inhibitor of RAS signaling. Additional functions have been proposed but not deeply investigated, due to its large size and complex domain structure. Whether somatic NF1 mutations can be used to guide clinical decisions is not known. Here, combining patient data, in vitro/in vivo models and protein biochemistry, we show that NF1 loss sensitizes cancer cells to T-DM1, the first approved ADC in breast cancer, through a novel, RAS-independent function on microtubular dynamics and repair. NF1 exhibits all biochemical properties of a bona fide Microtubule-Associated Protein (MAP) and specifically enhances intratubular repair, a recently discovered phenomenon whose regulation remains poorly characterized. NF1 loss results in mitotic defects and low-grade aneuploidy in cell lines and patients. Increased sensitivity to T-DM1 upon NF1 loss is confirmed in breast cancer patients analysed across institutions in Europe and USA. Our results define NF1 as a key regulatory factor for microtubular repair and the first ADC payload-associated predictive biomarker identified to date.

cancer biology↗