The BRD4 Inhibitor I-BET-762 Reduces HO-1 Expression in Macrophages and the Pancreas of Mice DOI Open Access

Ana S. Leal,

Karen T. Liby

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(18), P. 9985 - 9985

Published: Sept. 16, 2024

In pancreatic cancer, the tumor microenvironment (TME) accounts for up to 90% of mass. Pancreatitis, characterized by increased infiltration macrophages into pancreas, is a known risk factor cancer. The NRF2 (nuclear erythroid 2-related 2) transcription regulates responses oxidative stress and can promote cancer chemoresistance. also attenuates inflammation through regulation macrophage-specific genes. Heme oxygenase 1 (HO-1) expressed anti-inflammatory degrade heme, its expression dependent on translocation nucleus. stimulated with conditioned media from cells, HO-1 protein levels increased, which correlated higher in nuclear fraction. Significant differences macrophage were detected LSL-KrasG12D/+; Pdx-1-Cre (KC) mice, Nrf2 whole-body knockout (KO) mice wildtype pancreatitis. Since epigenetic modulation mechanism used tumors regulate TME, using small molecules as modulators activate immune recognition therapeutically desirable. When bromodomain inhibitor I-BET-762 was treat or pancreatitis, high reduced. This study shows that inhibitors be prevent physiological tumorigenesis.

Language: Английский

Unraveling the Connection Between Ion Channels and Pancreatic Stellate Cell Activation DOI Creative Commons
Julie Auwercx,

Mathilde Fourgeaud,

Alexis Lalot

et al.

Cellular Physiology and Biochemistry, Journal Year: 2025, Volume and Issue: 59(S1), P. 25 - 40

Published: Jan. 18, 2025

Quiescent pancreatic stellate cells (PSCs) represent only a very low proportion of the tissue, but their activation leads to stroma remodeling and fibrosis associated with pathologies such as chronic pancreatitis ductal adenocarcinoma (PDAC). PSC can be induced by various stresses, including acidosis, growth factors (PDGF, TGFβ), hypoxia, high pressure, or intercellular communication cancer cells. Activated targeting represents promising therapeutic strategy, little is known regarding molecular mechanisms underlying PSCs. Identification new biomarkers desmoplasia in PDAC could lead targets for exocrine disease treatments. Ion channels transporters are transmembrane proteins involved numerous physiological pathological processes, PDAC. They well act biosensors tissue microenvironment, they easily accessible drugs. However, role not fully understood. In this review, we briefly discuss activated PSCs pancreas inflammation (associated PDAC), describe specific ion (Ca2+, K+, Na+ Cl-) these processes light recent literature.

Language: Английский

Citations

1
Frontiers in pancreatic cancer on biomarkers, microenvironment, and immunotherapy DOI Creative Commons

Baofa Yu,

Shengwen Shao, Wenxue Ma

et al.

Cancer Letters, Journal Year: 2024, Volume and Issue: unknown, P. 217350 - 217350

Published: Nov. 1, 2024

Pancreatic cancer remains one of the most challenging malignancies to treat due its late-stage diagnosis, aggressive progression, and high resistance existing therapies. This review examines latest advancements in early detection, therapeutic strategies, with a focus on emerging biomarkers, tumor microenvironment (TME) modulation, integration artificial intelligence (AI) data analysis. We highlight promising including microRNAs (miRNAs) circulating DNA (ctDNA), that offer enhanced sensitivity specificity for early-stage diagnosis when combined multi-omics panels. A detailed analysis TME reveals how components such as cancer-associated fibroblasts (CAFs), immune cells, extracellular matrix (ECM) contribute therapy by creating immunosuppressive barriers. also discuss interventions target these components, aiming improve drug delivery overcome evasion. Furthermore, AI-driven analyses are explored their potential interpret complex data, enabling personalized treatment strategies real-time monitoring response. conclude identifying key areas future research, clinical validation regulatory frameworks AI applications, equitable access innovative comprehensive approach underscores need integrated, outcomes pancreatic cancer.

Language: Английский

Citations

6
64Cu Radiolabeled PDGFRβ-Targeting Affibody for PET Imaging in Pancreatic Cancer DOI
Li Zhao,

Ruiman Geng,

Y. H. Zhan

et al.

Molecular Pharmaceutics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 16, 2025

Pancreatic cancer is a malignant solid tumor that contains significant number of cancer-associated fibroblasts (CAFs). Clinical trials have confirmed CAF-targeted radionuclide therapy can suppress growth and extend the survival patients; therefore, quantifying CAFs by molecular imaging CAF biomarkers helpful for assessing disease progression therapeutic responses pancreatic cancer. In our previous study, we found platelet-derived factor receptor beta (PDGFRβ) was highly expressed on various fibroblast cells, novel affibody (ZPDGFRβ) with specific binding to PDGFRβ had been developed. Herein, verified high expression in tissues, ZPDGFRβ radiolabeled 64Cu obtain [64Cu]Cu-NOTA-ZPDGFRβ conjugate radiochemical purity higher than 95%. Biodistribution studies showed uptake reached peak 7.28 ± 0.92 at 6 h postinjection, tumor-to-pancreas ratio continuously increased reach 25.9 8.18 24 postinjection. Positron emission tomography (PET) ideal capability mice bearing both subcutaneous xenografts situ grafts. Our results demonstrated could be applied as promising PDGFRβ-targeted radiotracer PET

Language: Английский

Citations

0
LUNETR: Language-Infused UNETR for Precise Pancreatic Tumor Segmentation in 3D Medical Image DOI

Ziyang Shi,

R. Y. Zhang,

Xiajun Wei

et al.

Neural Networks, Journal Year: 2025, Volume and Issue: 187, P. 107414 - 107414

Published: March 15, 2025

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
Unveiling purine metabolism dysregulation orchestrated immunosuppression in advanced pancreatic cancer and concentrating on the central role of NT5E DOI Creative Commons
Junqian Zhang, Xiaobo Zhang, R. Wu

et al.

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

Published: April 1, 2025

The dismal efficacy of immunotherapy for Pancreatic cancer (PC) can be predominantly ascribed to its distinctive cold-tumor properties. by-products purine metabolic reprogramming are extensively engaged in tumor immune modulation, influencing the functions and recruitment cells molding an microenvironment that is propitious growth. We harnessed single-cell transcriptomics spatial concurrently analyze metabolism (PM) features PC microenvironment. quantitatively appraised PM traits diverse cell subsets via scoring algorithms such as AUCell Ucell. Moreover, development cell-cell interaction analysis elucidated alterations TME induced by dysregulation. Additionally, we defined disorder characteristics patients utilized this assess phenotypes prognoses patient population. Also, identified crucial intermediate genes impact establishment immunosuppressive environment within PC, validated them through sectioning co-culture experiments. Multi - dimensional transcriptome data unique heterogeneity microenvironment, which manifested fibroblasts demonstrating higher scores TME. Cellchat revealed malignant with elevated expression were concomitantly associated frequent interactions CAFs well high ligand-receptor pairs transcription factors. Spatial further corroborated finding. Furthermore, newly constructed criteria indicated levels a lack response Finally, study singular role NT5E immunosuppression resulting from PC. CCK8 invasion experiments following model demonstrated intervention targeting could reverse augmented malignancy co-cultured CAFs. potentially key target reversing "stiff-cancer" This demonstrates disorders impinge upon exacerbate engendered progression fibrosis. Therapeutic strategies or may offer ray hope advanced PDAC.

Language: Английский

Citations

0
Breaking Down Barriers in Drug Delivery by Stromal Remodeling Approaches in Pancreatic Cancer DOI
Ying Zhou, Yunxiao Ma,

Jingdan Sheng

et al.

Molecular Pharmaceutics, Journal Year: 2024, Volume and Issue: unknown

Published: July 24, 2024

Pancreatic cancer remains a formidable challenge in oncology due to its aggressive nature and limited treatment options. The dense stroma surrounding pancreatic tumors not only provides structural support but also presents barrier effective therapy, hindering drug penetration immune cell infiltration. This review delves into the intricate interplay between stromal components cells, highlighting their impact on resistance prognosis. Strategies for remodeling, including modulation of cancer-associated fibroblasts (CAFs), stellate cells (PSCs) activation states, targeting extracellular matrix (ECM) components, are examined potential enhance improve therapeutic efficacy. Integration remodeling with conventional therapies, such as chemotherapy immunotherapy, is discussed along emerging field intelligent nanosystems targeted delivery. comprehensive overview underscores importance offers insights promising avenues future research clinical translation.

Language: Английский

Citations

2
Cancer-associated fibroblasts: heterogeneity, tumorigenicity and therapeutic targets DOI Creative Commons

Kangzheng Lv,

Tianlin He

Molecular Biomedicine, Journal Year: 2024, Volume and Issue: 5(1)

Published: Dec. 16, 2024

Abstract Cancer, characterized by its immune evasion, active metabolism, and heightened proliferation, comprises both stroma cells. Although the research has always focused on parenchymal cells, non-parenchymal components must not be overlooked. Targeting cancer cells proven to a formidable challenge, yielding limited success broad scale. The tumor microenvironment(TME), critical niche for cell survival, presents novel way treatment. Cancer-associated fibroblast (CAF), as main component of TME, is dynamically evolving, dual-functioning stromal cell. Furthermore, their biological activities span entire spectrum development, metastasis, drug resistance, prognosis. A thorough understanding CAFs functions therapeutic advances holds significant clinical implications. In this review, we underscore heterogeneity elaborating origins, types function. Most importantly, elucidating direct or indirect crosstalk between extracellular matrix, emphasize tumorigenicity in cancer. Finally, highlight challenges encountered exploration list targeted therapies CAF, which have implications

Language: Английский

Citations

2
Architectural organization and molecular profiling of 3D cancer heterospheroids and their application in drug testing DOI Creative Commons

Boye Schnack Nielsen,

Natasha Helleberg Madsen, Jesper Larsen

et al.

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: July 1, 2024

3D cancer cell cultures have enabled new opportunities for replacing compound testing in experimental animals. However, most solid tumors are composed of multiple types, including fibroblasts. In this study we developed multicellular tumor heterospheroids and fibroblasts lines. We by combining HT-29, MCF-7, PANC-1 or SW480 with 1BR.3.G fibroblasts, which previously reported support spheroid formation. also tested fibroblast lines, MRC-5, GM00498 HIF, but was found to best form morphological similarity

Language: Английский

Citations

1
The importance of stroma and stromal sma expression in pancreatic ductal adenocarcinoma DOI Creative Commons
Gamze Akbaş, Pelin Bağcı

Turkish Journal of Pathology, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Pancreatic stellate cells (PSC) have been defined to be the key players in pancreatic fibrogenesis and carcinogenesis. They undergo myofibroblast-like differentiation, express α-smooth muscle actin (α-SMA), play a crucial role injury inflammation sites. This study aims evaluate relationship between α-SMA expression histopathological parameters of ductal adenocarcinoma (PDAC), investigate their association with prognosis.

Language: Английский

Citations

0