Biology subjects

Acedo, P.

Publications and source records attributed to Acedo, P..

4 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↗

bioRxiv2019

Protoporphyrin IX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and induces apoptosis in B-cell chronic lymphocytic leukaemia cells

p53 is a tumor suppressor, which belongs to the p53 family of proteins. The family consists of p53, p63 and p73 proteins, which share similar structure and function. Activation of wild-type p53 or TAp73 in tumors leads to tumor regression, and small molecules restoring the p53 pathway are in clinical development. Protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid, is a clinically approved drug applied in photodynamic diagnosis and therapy. PpIX induces p53- and TAp73-dependent apoptosis and inhibits TAp73/MDM2 and TAp73/MDM4 interactions. Here we demonstrate that PpIX is a dual inhibitor of p53/MDM2 and p53/MDM4 interactions and activates apoptosis in B-cell chronic lymphocytic leukaemia cells without illumination and without affecting normal cells. PpIX stabilizes p53 and TAp73 proteins, induces p53-downstream apoptotic targets and provokes cancer cell death at doses non-toxic to normal cells. Our findings open up new opportunities for repurposing PpIX for treating lymphoblastic leukaemias with wtTP53.

cancer biology↗

bioRxiv2018

Activation of TAp73 and inhibition of thioredoxin reductase for improved cancer therapy in TP53 mutant pancreatic tumors

The p73 is a tumor suppressor that compensates for p53 loss and induces apoptosis in tumors in response to genotoxic stress or small-molecule treatments.\n\nPancreatic ductal adenocarcinoma (PDAC) has a late onset of the disease, responds poorly to the existing therapies and has very low overall survival rates.\n\nHere, using drug-repurposing approach, we found that protoporphyrin IX (PpIX) and benzoporphyrin derivative monoacid ring A (BPD) activate p73 and induce apoptosis in pancreatic cancer cells. PpIX and BPD induce reactive oxygen species and inhibit thioredoxin reductase 1 (TrxR1). Thus, PpIX and BPD target cancer cells vulnerabilities namely activate TAp73 tumor suppressor and inhibit oncogenic TrxR1. Our findings, may contribute to faster repurposing of PpIX and BPD to treat pancreatic tumors.\n\nLay AbstractDespite the efforts, pancreatic cancer remains among the most aggressive tumors. Late diagnoses often linked with the asymptomatic disease progression make it extremely difficult to cure. We have used drugs that are already in clinics and applied in photodynamic therapy of cancer and showed that the compounds induce death of cancer cells. The mechanism is via activation of p73 tumor suppressor and inhibition oncogenic thioredoxin reductase. Molecules that in parallel induce two pathways leading to cell death might be very promising candidates for improved cancer therapy in pancreatic cancer patients.

cancer biology↗

bioRxiv2018

Reactivation of TAp73 tumor suppressor by protoporphyrin IX, a metabolite of aminolevulinic acid, compensates for p53 loss and induces apoptosis in TP53-deficient cancer cells.

BackgroundThe p73 protein is a tumor suppressor that shares structural and functional similarity with p53. p73 is expressed in two major isoforms; the TA isoform that interacts with p53 pathway, thus acting as tumor suppressor and the N-terminal truncated {Delta}N isoform that inhibits TAp73 and p53 and thus, acts as an oncogene.\n\nResultsBy employing a drug repurposing approach, we found that protoporphyrin IX (PpIX), a metabolite of aminolevulinic acid (ALA) applied in photodynamic therapy of cancer, stabilizes TAp73 and activates TAp73-dependent apoptosis in cancer cells lacking p53. The mechanism of TAp73 activation is via disruption of TAp73/MDM2 and TAp73/MDMX interactions and inhibition of TAp73 degradation by ubiquitin ligase Itch.\n\nConclusionOur findings may in future contribute to the successful repurposing of PpIX into clinical practice.

cancer biology↗