A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer DOI Creative Commons
Juliana Calheiros, Rita Silva, Filipa Barbosa

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: April 24, 2025

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is among the cancer types with poorest prognosis and survival rates primarily due to resistance standard-of-care therapies, including gemcitabine (GEM) olaparib. Particularly, wild-type (wt)BRCA tumours, most prevalent in PDAC, are more resistant DNA-targeting agents like olaparib, restraining their clinical application. Recently, we disclosed a monoterpene indole alkaloid derivative (BBIT20) as new inhibitor of homologous recombination (HR) DNA repair anticancer activity breast ovarian cancer. Since inhibition enhances sensitivity cells chemotherapy, aimed investigate potential BBIT20 against particularly carrying wtBRCA. Methods In vitro vivo PDAC models, human cell lines (including GEM-resistant cells), patient-derived organoids xenograft mice were used evaluate BBIT20, alone combination GEM or Disruption BRCA1-BARD1 interaction by was assessed co-immunoprecipitation, immunofluorescence yeast two-hybrid assay. Results The potent antiproliferative superior demonstrated regardless BRCA status, inducing cycle arrest, apoptosis, damage, while downregulating HR. disruption double-strand breaks further reinforced non-homologous end joining (NHEJ) suppression. heterodimer confirmed cells, showed antiproliferative, anti-migratory anti-invasive activity, overcoming inhibiting multidrug P-glycoprotein, upregulating intracellular GEM-transporter ENT1, resistance-related microRNA-20a metabolism enzymes RRM1/2. Furthermore, did not induce cells. It inhibited growth organoids, repressing HR, potentiating olaparib cytotoxicity. enhancement antitumor PDAC. Notably, it hindered tumour liver metastasis formation, improving orthotopic its stroma-targeting agent, reducing fibrotic extracellular matrix desmoplasia, associated an immune response depleting PD-L1 expression tissues, renders even appealing for therapy, immunotherapy. Conclusion These findings underscore great novel multifaceted drug candidate treatment.

Language: Английский

Deciphering the mechanisms of PARP inhibitor resistance in prostate cancer: Implications for precision medicine DOI
Cheng Wang, Xiaoran Han,

Shaoqiu Kong

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2025, Volume and Issue: 185, P. 117955 - 117955

Published: March 13, 2025

Language: Английский

Citations

0
Mechanistic role of stromal cancer-associated fibroblasts in tumorigenesis and brain metastasis: highlighting drug resistance and targeted therapy DOI
Md Rashedunnabi Akanda,

Umme Lubaba,

Md Khalesur Rahman

et al.

Pathology - Research and Practice, Journal Year: 2025, Volume and Issue: unknown, P. 155918 - 155918

Published: March 1, 2025

Language: Английский

Citations

0
Extracellular vesicles in cancer´s communication: messages we can read and how to answer DOI Creative Commons
Alena Semerádtová, Michaela Liegertová, Regina Herma

et al.

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: March 19, 2025

Abstract Extracellular vesicles (EVs) are emerging as critical mediators of intercellular communication in the tumor microenvironment (TME), profoundly influencing cancer progression. These nano-sized vesicles, released by both and stromal cells, carry a diverse cargo proteins, nucleic acids, lipids, reflecting dynamic cellular landscape mediating intricate interactions between cells. This review provides comprehensive overview biogenesis, composition, functional roles EVs cancer, highlighting their significance basic research clinical applications. We discuss how cells manipulate EV biogenesis pathways to produce enriched with pro-tumorigenic molecules, explore specific contributions key hallmarks such angiogenesis, metastasis, immune evasion, emphasizing role shaping TME driving therapeutic resistance. Concurrently, we submit recent knowledge on can serve valuable source biomarkers for minimally invasive liquid biopsies, its potential, particularly targeted drug delivery vehicles immunomodulatory agents, showcasing promise enhancing efficacy safety treatments. By deciphering messages carried EVs, gain deeper understanding biology develop more effective strategies early detection, therapy, immunotherapy, paving way new era personalized precise medicine potential significantly improve patient outcomes.

Language: Английский

Citations

0
Multidimensional transcriptomics based to illuminate the mechanisms of taurine metabolism in immune resistance of pancreatic cancer DOI Creative Commons

Zongshuai Qin,

Gui‐Xiang Huang, Jian Xu

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: March 31, 2025

Pancreatic cancer, a highly malignant tumor of the digestive system, is characterized by microenvironment with high degree immunosuppression. This immunosuppressive property poses significant challenges, as it hampers effective infiltration immune cells and impairs their ability to exert cytotoxic effects. The metabolic process taurine has emerged crucial factor in modulating functions activities cells. Intervening metabolism holds potential reshape microenvironment, thereby enhancing recognize eliminate To explore therapeutic relationship between disorders pancreatic cancer immunotherapy, we employed multiple software packages, including "Seurat", "DoubletFinder", "Harmony", "GSVA", "CellChat" analyze single-cell data spatial transcriptomic cancer. In present study, four distinct cell subsets, namely RPS4Y1+ cells, LYZ+ CPE+ MKI67+ were identified for first time. CNV score highlighted role within Through cell-communication analysis, crosstalk among fibroblasts, CD8+ T was identified, offering novel insights into immunotherapy strategies, which strengthened co-localization analysis transcriptomics. Furthermore, conducting combined survival data, LY6D target. co-culture experiments uncovered underlying mechanism regulating imbalance establishment "taurine-immune crosstalk" criteria this study effectively paves way immunotherapy. conclusion, current research underscores significance Targeting may represent approach reversing "stiff-cancer" characteristics

Language: Английский

Citations

0
Understanding Merkel Cell Carcinoma: Pathogenic Signaling, Extracellular Matrix Dynamics, and Novel Treatment Approaches DOI Open Access
Maria Konstantaraki, Aikaterini Berdiaki, Monica Neagu

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(7), P. 1212 - 1212

Published: April 2, 2025

Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer, driven by either polyomavirus (MCPyV) integration or ultraviolet (UV)-induced mutations. In MCPyV-positive tumors, viral T antigens inactivate tumor suppressors pRb and p53, while virus-negative MCCs harbor UV-induced mutations that activate similar oncogenic pathways. Key signaling cascades, including PI3K/AKT/mTOR MAPK, support proliferation, survival, resistance to apoptosis. Histologically, MCC consists of small round blue cells with features, high mitotic rate, necrosis. The microenvironment (TME) plays central role in disease progression immune escape. It comprises mix tumor-associated macrophages, regulatory cytotoxic cells, elevated expression checkpoint molecules such as PD-L1, contributing an immunosuppressive niche. extracellular matrix (ECM) within the TME rich proteoglycans, collagens, metalloproteinases (MMPs), facilitating adhesion, invasion, interaction stromal cells. ECM remodeling integrin-mediated further promote evasion therapy resistance. Although inhibitors targeting PD-1/PD-L1 have shown promise treating MCC, remains major hurdle. Therapeutic strategies concurrently target TME-through inhibition components, MMPs, integrin signaling-may enhance responses improve clinical outcomes.

Language: Английский

Citations

0
Revisiting the role of cancer-associated fibroblasts in tumor microenvironment DOI Creative Commons

Xiaolei Lan,

Wenyang Li, Kai Zhao

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 17, 2025

Cancer-associated fibroblasts (CAFs) are integral components of the tumor microenvironment playing key roles in progression, metastasis, and therapeutic resistance. However, challenges persist understanding their heterogeneity, origin, functional diversity. One major obstacle is lack standardized naming conventions for CAF subpopulations, with current systems failing to capture full complexity. Additionally, identification CAFs hindered by absence specific biomarkers, limiting precision diagnostic strategies. In vitro culture conditions often fail maintain vivo characteristics CAFs, which complicates study translation findings clinical practice. Although detection methods, such as antibodies, mRNA probes, single-cell transcriptomics, offer insights into biology, they standardization provide reliable quantitative measures. Furthermore, dynamic interactions between cells, immune cells within TME remain insufficiently understood, role evasion therapy resistance an area ongoing research. Understanding how influence drug response essential developing more effective cancer therapies. This review aims in-depth analysis research, propose future research directions, emphasize need improved CAF-targeted By addressing these gaps, it seeks highlight potential targets overcoming enhancing efficacy treatments.

Language: Английский

Citations

0
Unravelling Paclitaxel Resistance in Gastric Cancer: The Role of Small Extracellular Vesicles in Epithelial Mesenchymal Transition and Extracellular Matrix Remodelling DOI Open Access

G. Panzetta,

Annalisa Schirizzi,

Francesco Balestra

et al.

Cancers, Journal Year: 2025, Volume and Issue: 17(8), P. 1360 - 1360

Published: April 18, 2025

Background: Gastric cancer (GC) is a highly aggressive disease often complicated by resistance to chemotherapy agents like paclitaxel (PTX), which targets microtubules induce apoptosis. Resistance arises through complex molecular mechanisms, including the overexpression of pro-angiogenic factors (VEGFA, ANG-2), activation survival pathways (PDGFRβ, PPARγ), and epithelial-mesenchymal transition (EMT) driven proteins such as VIM, E-CAD, N-CAD, FLOT-1. The extracellular matrix (ECM), regulated COL1A1 influenced PPARγ, acts physical barrier drug penetration. Small vesicles (sEVs) have emerged critical mediators intercellular communication may influence these pathways. Methods: This study investigated role sEVs isolated from metastatic GC patients treated with Ramucirumab PTX. Patients were stratified progression-free (PFS) into rapidly progressing (RP) controlled (CD) groups. applied HCEC-1CT HEPA-RG cell lines. Cell viability assays, gene protein expression analyses, bioinformatic studies conducted assess impact on resistance-related markers. Results: Results showed that CD reduced markers associated resistance, while RP increased markers, promoting angiogenesis, EMT, ECM remodeling. These changes correlated enhanced phenotypes. Bioinformatic analyses confirmed modulate inflammation, dynamics, EMT Conclusions: In conclusion, significantly chemoresistance tumor progression. Targeting sEV-mediated signaling offer novel therapeutic strategies overcome improve treatment outcomes in gastric cancer.

Language: Английский

Citations

0
A first-in-class inhibitor of homologous recombination DNA repair counteracts tumour growth, metastasis and therapeutic resistance in pancreatic cancer DOI Creative Commons
Juliana Calheiros, Rita Silva, Filipa Barbosa

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2025, Volume and Issue: 44(1)

Published: April 24, 2025

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is among the cancer types with poorest prognosis and survival rates primarily due to resistance standard-of-care therapies, including gemcitabine (GEM) olaparib. Particularly, wild-type (wt)BRCA tumours, most prevalent in PDAC, are more resistant DNA-targeting agents like olaparib, restraining their clinical application. Recently, we disclosed a monoterpene indole alkaloid derivative (BBIT20) as new inhibitor of homologous recombination (HR) DNA repair anticancer activity breast ovarian cancer. Since inhibition enhances sensitivity cells chemotherapy, aimed investigate potential BBIT20 against particularly carrying wtBRCA. Methods In vitro vivo PDAC models, human cell lines (including GEM-resistant cells), patient-derived organoids xenograft mice were used evaluate BBIT20, alone combination GEM or Disruption BRCA1-BARD1 interaction by was assessed co-immunoprecipitation, immunofluorescence yeast two-hybrid assay. Results The potent antiproliferative superior demonstrated regardless BRCA status, inducing cycle arrest, apoptosis, damage, while downregulating HR. disruption double-strand breaks further reinforced non-homologous end joining (NHEJ) suppression. heterodimer confirmed cells, showed antiproliferative, anti-migratory anti-invasive activity, overcoming inhibiting multidrug P-glycoprotein, upregulating intracellular GEM-transporter ENT1, resistance-related microRNA-20a metabolism enzymes RRM1/2. Furthermore, did not induce cells. It inhibited growth organoids, repressing HR, potentiating olaparib cytotoxicity. enhancement antitumor PDAC. Notably, it hindered tumour liver metastasis formation, improving orthotopic its stroma-targeting agent, reducing fibrotic extracellular matrix desmoplasia, associated an immune response depleting PD-L1 expression tissues, renders even appealing for therapy, immunotherapy. Conclusion These findings underscore great novel multifaceted drug candidate treatment.

Language: Английский

Citations

0