Biology subjects

Nicolaci, A.

Publications and source records attributed to Nicolaci, A..

3 recordsLinked to original sources

bioRxiv2026

circPMS1-mediated LIM protein scaffolding promotes cytoskeletal remodeling and melanoma metastasis

Circular RNAs (circRNAs) have been implicated in diverse biological processes and diseases such as cancer; however, their functional roles in tumor biology remain incompletely understood. Here, we identify circPMS1 as an aberrantly upregulated, pro-metastatic circRNA in melanoma. Overexpression and silencing studies revealed that circPMS1 promotes migration and invasion of non-transformed melanocytes and melanoma cells, enhances metastasis in xenograft models, and drives spontaneous dissemination and lymph node metastases in a genetically engineered melanoma mouse model. circPMS1 pro-metastatic activity depends on its circularization and is mediated by a putative secondary structure spanning the back-splice junction and the canonical start codon of the linear PMS1 mRNA. Proteomic analysis identified LIM domain proteins, including ABLIM1, LMO7, and PDLIM7, as circPMS1-bound factors. Mechanistic studies demonstrate that circPMS1 scaffolds these LIM proteins, enhancing their association with actin filaments inducing focal adhesion and cytoskeletal remodeling. This remodeling is associated with RhoA activity, and inhibition of the RhoA pathway attenuates circPMS1-induced migration. Together, these findings establish circPMS1 as a pro-metastatic circRNA that drives melanoma progression by scaffolding LIM domain proteins and regulating cytoskeletal dynamics and cell motility.

Cancer Biology↗

bioRxiv2026

Quinolinic acid phosphoribosyl transferase moonlights as an apoptosis regulator to empower lung cancer progression

Although nicotinamide adenine dinucleotide (NAD) metabolism is fundamental for cancer cell survival, the role of the de novo NAD biosynthetic pathway, particularly in non-small cell lung cancer (NSCLC), remains largely unknown. Here, we describe a non-canonical role for the rate-limiting enzyme in de novo NAD+ biosynthesis, quinolinate phosphoribosyltransferase (QPRT), in NSCLC progression. We show that QPRT is highly expressed in late-stage tumors and required for NSCLC growth; however, its suppression does not change NAD levels or elicit compensatory NAD biosynthetic activity. Instead, QPRT interacts with caspase-3 and suppresses its activation, protecting NSCLC cells from apoptosis. This reveals a moonlighting function for QPRT in apoptosis regulation independent of its enzymatic activity in tryptophan catabolism. Together, these findings, redefine QPRT as a protein with dual functionality and reveal it as a potential therapeutic target in NSCLC, highlighting the importance of non-canonical roles of metabolic enzymes in cancer biology. SignificanceThis study reveals that QPRT supports NSCLC progression by directly inhibiting caspase-3-mediated apoptosis independent of NAD biosynthesis, redefining its role and highlighting non-enzymatic functions of metabolic enzymes as therapeutic targets.

cancer biology↗

bioRxiv2024

Targeted degradation of the HPV oncoprotein E6 reduces tumor burden in cervical cancer

Human Papilloma Virus (HPV)-related cancers are a global health burden, yet there are no targeted therapies available for chronically infected patients. The HPV protein E6 is essential for HPV-mediated tumorigenesis and immune evasion, making it an attractive target for antiviral drug development. In this study, we developed an E6-targeting Proteolysis Targeting Chimera (PROTAC) that inhibits the growth of HPV(+) tumors. To develop E6 antagonists, we generated a panel of nanobodies targeting E6 proteins derived from the oncogenic HPV16 subtype. The highest affinity E6 nanobody, A5, was fused to Von Hippel Lindau protein (VHL) to generate a PROTAC that degrades E6 (PROTACE6). Mutational rescue experiments validated specific degradation via the CRL2VHL E3 ligase. Intralesional administration of the PROTACE6 using a clinically viable DNA vaccine reduced tumor burden in an immunocompetent mouse model of HPV(+) cancer. The inhibitory effect of the PROTACE6 was abrogated by CD4+ and CD8+ T-cell depletion, indicating that the antitumor function of the PROTACE6 relies in part on a host immune response. Overall, these results suggest that the targeted degradation of E6 inhibits its oncogenic function and stimulates a robust immune response against HPV(+) tumors, opening new opportunities for virus-specific therapies in the treatment of HPV-related cancers.

molecular biology↗