Biology subjects

Noguera, A.

Publications and source records attributed to Noguera, A..

3 recordsLinked to original sources

bioRxiv2026

Diet-induced macrophage-driven inflammation fuels pancreatic plasticity and aggressiveness

High-fat diet (HFD) and obesity are increasingly recognized as risk factors of pancreatic ductal adenocarcinoma (PDAC), yet the mechanisms by which dietary fat contribute to oncogenic transformation remain elusive. Using an inducible acinar-specific KrasG12V/Trp53-loss genetically-engineered mouse model of PDAC, we established early-and late-onset protocols to assess age-dependent susceptibility to HFD. Specifically, HFD accelerated tumorigenesis with poorer prognosis in early-onset mice and, strikingly, enabled full PDAC development in late-onset adult mice otherwise resistant to oncogenic transformation. Tumors arising under HFD activated a distinct transcriptional and epigenetic state enriched in pathways or genes related to stemness, plasticity, and metastatic competence, which was maintained even in tumor-derived cell lines. Mechanistically, fatty acid-educated macrophages secreted the cathelicidin antimicrobial peptide (CAMP), activating P2X purinoceptor 7 (P2RX7) signaling in tumor cells to drive a highly plastic, immune-evasive phenotype reinforced by the expression of the peptidoglycan recognition protein 1 (PGLYRP1), further shielding tumor cells from macrophage phagocytosis. Functionally, HFD-induced tumors displayed enhanced metastatic potential independent of host context. Analysis of 164 human PDAC samples revealed that elevated body-mass index (BMI) was associated to a conserved CAMP-P2RX7-CXCR4 signature, maintained despite weight loss during disease progression. Together, these findings uncover a diet-imprinted macrophage-tumor cell circuit that promotes transformation and accelerates PDAC progression, positioning it as a therapeutic vulnerability in obesity-associated pancreatic cancer. Statement of significanceHigh-fat diet induces pancreatic tumorigenesis in adult tissue, driving metastatic competence and a plastic state, and ultimately engages a macrophage-derived CAMP-P2RX7 circuit that reinforces immune evasion and accelerates PDAC progression.

cancer biology↗

bioRxiv2025

Adeno-associated viruses (AAVs) induce dose-dependent neonatal ventriculomegaly following intracerebroventricular administration

Cell-type-specific expression of synthetic/endogenous proteins or genetic sequences has significantly advanced our understanding of the central nervous system (CNS). Adeno-associated virus (AAV)-delivery to cerebrospinal fluid (CSF) mediates transfection of target cells to enable sustained delivery of secretory proteins into the CSF, offering promising avenues for both CNS therapy and mechanistic studies. However, despite the advantages afforded by AAV tropism-based cellular selectivity and transgene delivery, both preclinical studies and clinical trials report short- and long-term adverse effects, particularly immune activation. Especially relevant for CSF biology, CNS immune insults raise the risk of CSF dysregulation, including hydrocephalus. These risks may be exacerbated in pediatric populations, where ongoing CNS development, including immature meninges, choroid plexus (ChP), and skull structures, may further impair any ability to compensate for CSF dysregulation. To systematically address these risks and provide guidelines for minimizing CNS immune insults by AAVs, we test the dose-dependent effects of intracerebroventricular (ICV) injections of 3 AAV serotypes (AAV2/5, AAV2/4, and AAV.PHP.eB) to neonatal (P0.5) CD1 mouse pups. Histological analysis verified AAV2/5 tropism limited to ChP epithelial cells (CPECs), whereas AAV.PHP.eB transfected both CPECs and ependymal regions. By contrast, AAV2/4 shows limited transfection in the brain. Further, we find that ICV injections of all 3 AAV serotypes at the high dose (4x109 genome copy GC/pup) induced ventriculomegaly by P7.5, while the low dose (1x109 GC/pup) was well tolerated. Additionally, high-dose AAV2/5 tropism became more permissive, transfecting the ChP and also ependymal cells and some neurons. Longitudinal MRI of P0.5 pups with high-dose AAV2/5 ICV injections highlighted quick progression of ventriculomegaly. CSF ELISA analysis detected elevated pro-inflammatory cytokine CCL2 in AAV2/5 and AAV2/4 high-dose groups, indicating CNS inflammation. Moreover, decreased CSF TTR concentrations in high-dose groups suggest ChP dysfunction. We further revealed that earlier in utero high-dose ICV AAV2/5 injections at E13.5 induced even more severe ventriculomegaly and that adult animals were also susceptible to ventriculomegaly after high-dose AAV ICV delivery. Taken together, our data emphasize critical safety considerations of CSF-based AAV delivery, particularly during brain development. Further, these results call for an optimized dosage for perinatal ICV AAV applications. HighlightsO_LICSF-administration of AAVs results in unique cellular tropism in neonatal brains. C_LIO_LIIntracerebroventricular AAV delivery induces dose-dependent neonatal ventriculomegaly. C_LIO_LINeonatal ventriculomegaly by AAV overdose develops quickly and progressively. C_LIO_LIAAV overdose ventriculomegaly correlates with ChP/CSF dyshomeostasis and inflammation. C_LIO_LIAdult and embryonic brains are also susceptible to dose-dependent AAV-induced ventriculomegaly. C_LI

neuroscience↗

bioRxiv2025

METTL3-mediated m6A modification of DNMT1 enhances ovarian cancer progression

High-grade serous carcinoma (HGSC), the most lethal subtype of ovarian cancer, is often diagnosed at advanced stages owing to its asymptomatic progression and lack of early detection markers. In this study, we identified a critical oncogenic role of the RNA methyltransferase METTL3 and the N6-methyladenosine (m6A) RNA modification pathway in HGSC. Depletion of METTL3 or its binding partner METTL14 impairs ovarian cancer proliferation and tumor progression. Mechanistically, m6A deposition enhances the translation of DNA methyltransferase DNMT1, an epigenetic repressor that silences tumor suppressor genes. Pharmacologic inhibition of DNMT1 led to DNA hypomethylation and upregulation of the tumor suppressors TNFAIP3 and FBXO32. Consistently, METTL3 depletion also increased the expression of these genes supporting a model in which METTL3 sustains oncogenesis by maintaining DNMT1 protein levels and repressing anti-tumor pathways. These findings position METTL3-mediated RNA modifications and DNMT1 as promising therapeutic targets in HGSC.

cancer biology↗