Biology subjects

De Menna, M.

Publications and source records attributed to De Menna, M..

6 recordsLinked to original sources

bioRxiv2026

Iron Metabolism as a Therapeutic Vulnerability in Stem Cell-Like Castration-Resistant Prostate Cancer

Prostate cancer is the second most common malignancy among men, with androgen deprivation therapy (ADT) serving as the standard treatment due to the hormone sensitivity of prostate tumors. However, therapeutic resistance frequently develops, leading to castration-resistant prostate cancer (CRPC), an aggressive and lethal disease. A recently defined subtype, stem cell-like CRPC (CRPC-SCL), accounts for approximately 25% of CRPC cases and demonstrates poor responsiveness to ADT. CRPC-SCL is characterized by the expression of Cluster of Differentiation 44 (CD44), a glycoprotein that promotes hyaluronic acid binding and uptake. Within CRPC-SCL patient-derived xenograft (PDX) model, CD44 high (CD44hi) cells exhibit enhanced tumorigenicity and proliferative capacity. Importantly, iron metabolism emerges as a critical regulator of this population: CD44hi cells maintain elevated intracellular iron, which sustains CD44 expression and stem cell-like properties by modulating H3K9me2 modification. Leveraging this vulnerability, inhibition of the iron-regulatory factor NRF2 was shown to increase intracellular free iron and selectively induce ferroptosis in CD44hi cells. These findings highlight the therapeutic potential of targeting iron metabolism to induce ferroptosis as a novel treatment strategy for CRPC-SCL.

cancer biology↗

bioRxiv2025

A Human Alveolus-on-Chip Recapitulates SARS-CoV-2-mediated Lung Injury in an Organ-relevant Context for Pre-clinical Applications

Respiratory viruses pose a constant threat to public health as highlighted by the pandemic outbreak of COVID-19. The most severe manifestation of COVID-19 is observed in the distal lung, where SARS-CoV-2 infection can result in massive inflammation and barrier breakdown. To date, few therapies are approved for clinical use in COVID-19 patients partially due to the lack of highly translational pre-clinical models of the alveoli. Human-derived microphysiological systems pose a promising new class of in vitro models to study viral infection in a relevant context. Therefore, we aimed to develop a Lung-on-Chip (LOC) model for studying SARS-CoV-2 infection at the alveolar barrier. Using an immortalized alveolar epithelial cell line, AXiAEC, and human lung microvascular endothelial cells (hLMVEC) we established a SARS-CoV-2 infection model on a LOC system. The LOC models the alveolar epithelial/endothelial barrier under physiological breathing motion. Our results demonstrated that AXiAEC maturation at the air-liquid interface (ALI) is essential for SARS-CoV-2 infection. SARS-CoV-2 infected the breathing LOC model and induced breakdown of the air-blood barrier. Finally, we evaluated the application of the LOC SARS-CoV-2 infection model for efficacy testing and demonstrated the antiviral effect of remdesivir. Drug treatment not only inhibited viral replication but also protected the alveolar barrier from damage and partially reverted SARS-CoV-2-mediated transcriptional dysregulation in AXiAEC. This novel LOC infection model recapitulates aspects of COVID-19. Our results highlight the importance of physiological cues such as ALI and stretch to accurately model host-pathogen interactions in the distal lung. Application of LOC models in pre-clinical drug testing may facilitate candidate compound selection at an early stage, allowing the allocation of resources to a few promising candidate compounds raising the potential to accelerate drug development and reduce costs and animal testing.

cell biology↗

bioRxiv2023

Mechano-signaling of prostate tumor initiating cells facilitates their tropism to stiff metastatic niche

Analysis of clinical datasets indicate that cancer stem-like cells/tumor-initiating cells (CSCs/TICs) derived from prostate cancer (PCa) patients display an elevated expression of genes for cell-matrix interactions, cell adhesion proteins and of the putative mechanotransducer TAZ. Here we combined measurements on the cellular mechano-responses to matrix stiffness, including cell-generated forces, zebrafish and PDX-derived organoid models, to show that mechanotransduction serves as a key determinant for PCa CSC maintenance during metastatic onset. The {beta}1-integrin-ILK-CDC42-N-Wasp dependent cytoskeletal tension and TAZ nucleus-translocation mediate this mechano-signaling axis. As a result, expression of the stemness genes NANOG and OCT4 are induced, leading to metastatic tumor initiation. It is further demonstrated that pharmaceutical perturbation of this mechano-signaling using a novel YAP/TAZ inhibitor K975 constrains PCa metastasis in zebrafish, and development of PDX-derived organoids. Our data highlights the essential role of mechanotransduction in PCa aggressiveness, thereby underlying this pathway as a therapeutic target for future studies.

cancer biology↗

bioRxiv2021

Network-based identification and pharmacological targeting of host cell master regulators induced by SARS-CoV-2 infection

Precise characterization and targeting of host cell transcriptional machinery hijacked by SARS-CoV-2 remains challenging. To identify therapeutically targetable mechanisms that are critical for SARS-CoV-2 infection, here we elucidated the Master Regulator (MR) proteins representing mechanistic determinants of the gene expression signature induced by SARS-CoV-2. The analysis revealed coordinated inactivation of MR-proteins linked to regulatory programs potentiating efficiency of viral replication (detrimental host MR-signature) and activation of MR-proteins governing innate immune response programs (beneficial MR-signature). To identify MR-inverting compounds capable of rescuing activity of inactivated host MR-proteins, with-out adversely affecting the beneficial MR-signature, we developed the ViroTreat algorithm. Overall, >80% of drugs predicted to be effective by this methodology induced significant reduction of SARS-CoV-2 infection, without affecting cell viability. ViroTreat is fully generalizable and can be extended to identify drugs targeting the host cell-based MR signatures induced by virtually any pathogen.

microbiology↗

bioRxiv2020

GATA3 and MDM2 are synthetic lethal in estrogen receptor-positive breast cancers

Synthetic lethal interactions, where the simultaneous but not individual inactivation of two genes is lethal to the cell, have been successfully exploited to treat cancer. GATA3 is frequently mutated in estrogen receptor (ER)-positive breast cancers and its deficiency defines a subset of patients with poor response to hormonal therapy and poor prognosis. However, GATA3 is not targetable. Here we show that GATA3 and MDM2 are synthetically lethal in ER-positive breast cancer. Depletion and pharmacological inhibition of MDM2 induce apoptosis in GATA3-deficient models in vitro, in vivo and in patient-derived organoids (PDOs) harboring GATA3 somatic mutation. The synthetic lethality requires p53 and acts via the PI3K/Akt/mTOR pathway. Our results present MDM2 as a novel therapeutic target in the substantial cohort of ER-positive, GATA3-mutant breast cancer patients. With MDM2 inhibitors widely available, our findings can be rapidly translated into clinical trials to evaluate in-patient efficacy.

cancer biology↗

bioRxiv2020

Patient-derived xenografts and organoids model therapy response in prostate cancer

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe a novel androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naive, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbours BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modelled in vivo. Comparison of the treatment-naive PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.

cancer biology↗