From precursor to cancer: decoding the intrinsic and extrinsic pathways of pancreatic intraepithelial neoplasia progression DOI
Sarah E. Graham, Mariia Dmitrieva, Débora B. Vendramini‐Costa

и другие.

Carcinogenesis, Год журнала: 2024, Номер 45(11), С. 801 - 816

Опубликована: Ноя. 1, 2024

This review explores the progression of pancreatic intraepithelial neoplasia (PanIN) to ductal adenocarcinoma through a dual lens intrinsic molecular alterations and extrinsic microenvironmental influences. PanIN development begins with Kirsten rat sarcoma viral oncogene (KRAS) mutations driving initiation. Key additional in cyclin-dependent kinase inhibitor 2A (CDKN2A), tumor protein p53 (TP53), mothers against decapentaplegic homolog 4 (SMAD4) disrupt cell cycle control genomic stability, crucial for from low-grade high-grade dysplasia. Additional neoplastic cells, including epigenetic modifications chromosomal alterations, can further contribute progression. In parallel these microenvironment, fibroblast activation, extracellular matrix remodeling, immune modulation, plays pivotal role initiation Crosstalk between stromal cells influences nutrient support evasion, contributing development, growth, survival. underscores intricate interplay cell-intrinsic drivers cell-extrinsic factors, shaping predisposition, initiation, Future research aims unravel interactions develop targeted therapeutic strategies early detection techniques, aiming alleviate severe impact cancer by addressing both genetic predispositions environmental

Язык: Английский

Determining the ERK-regulated phosphoproteome driving KRAS-mutant cancer DOI
Jennifer E. Klomp, J. Nathaniel Diehl, Jeffrey A. Klomp

и другие.

Science, Год журнала: 2024, Номер 384(6700)

Опубликована: Июнь 6, 2024

To delineate the mechanisms by which ERK1 and ERK2 mitogen-activated protein kinases support mutant KRAS–driven cancer growth, we determined ERK-dependent phosphoproteome in KRAS-mutant pancreatic cancer. We that share near-identical signaling transforming outputs KRAS-regulated is driven nearly completely ERK. identified 4666 phosphosites on 2123 proteins, of 79 66%, respectively, were not previously associated with ERK, substantially expanding depth breadth phosphorylation events revealing a considerably more complex function for ERK established controls highly dynamic converges cyclin-dependent kinase regulation RAS homolog guanosine triphosphatase (RHO GTPase). Our findings establish most comprehensive molecular portrait drives KRAS-dependent growth.

Язык: Английский

Процитировано

23
Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer DOI
Caitlin A. McIntyre, Adrien Grimont, Jiwoon Park

и другие.

Cancer Cell, Год журнала: 2024, Номер 42(9), С. 1614 - 1629.e5

Опубликована: Авг. 29, 2024

Язык: Английский

Процитировано

19
A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer DOI
Anupriya Singhal,

Hannah C. Styers,

Jonathan Rub

и другие.

Cancer Discovery, Год журнала: 2024, Номер 14(11), С. 2122 - 2134

Опубликована: Июль 5, 2024

Abstract Intratumoral heterogeneity in pancreatic ductal adenocarcinoma (PDAC) is characterized by a balance between basal and classical epithelial cancer cell states, with dominance associating chemoresistance dismal prognosis. Targeting oncogenic KRAS, the primary driver of cancer, shows early promise clinical trials, but efficacy limited acquired resistance. Using genetically engineered mouse models patient-derived xenografts, we find that PDAC cells are highly sensitive to KRAS inhibitors. Employing fluorescent bioluminescent reporter systems, longitudinally track cell-state dynamics vivo reveal rapid, inhibitor–induced enrichment state. Lineage tracing uncovers these enriched reservoir for disease relapse. Genetic or chemotherapy-mediated ablation state synergistic inhibition, providing preclinical proof concept this therapeutic strategy. Our findings motivate combining state–directed therapies inhibitors deepen responses counteract resistance cancer. Significance: hold We acutely resistant inhibition serves as alongside deepens responses, revealing potent See related commentary Marasco Misale, p. 2018

Язык: Английский

Процитировано

13
KRAS Oncoprotein Signaling in Cancer DOI
Piro Lito

New England Journal of Medicine, Год журнала: 2025, Номер 392(3), С. 296 - 298

Опубликована: Янв. 15, 2025

Язык: Английский

Процитировано

2
RAS signaling in carcinogenesis, cancer therapy and resistance mechanisms DOI Creative Commons

Xiaojuan Yang,

Hong Wu

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Ноя. 9, 2024

Variants in the RAS family (HRAS, NRAS and KRAS) are among most common mutations found cancer. About 19% patients with cancer harbor mutations, which typically associated poor clinical outcomes. Over past four decades, KRAS has long been considered an undruggable target due to absence of suitable small-molecule binding sites within its mutant isoforms. However, recent advancements drug design have made RAS-targeting therapies viable, particularly approval direct

Язык: Английский

Процитировано

7
Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells DOI Creative Commons
Chuan Wang,

Ya-Chin Hou,

Yi‐Kai Hong

и другие.

Molecular Cancer, Год журнала: 2025, Номер 24(1)

Опубликована: Янв. 18, 2025

Oncogenic KRAS mutations are present in approximately 90% of pancreatic ductal adenocarcinoma (PDAC). However, Kras mutation alone is insufficient to transform precancerous cells into metastatic PDAC. This study investigates how KRAS-mutated epithelial acquire the capacity escape senescence or even immune clearance, thereby progressing advanced Single-cell RNA sequencing and analysis primary PDAC tumors were conducted. Genetically engineered pancreas-specific Kras-mutated, dual specificity phosphatase-2 (Dusp2) knockout mouse models established. Human cancer cell lines used for vitro assessment characteristics. Tumor progression was studied via pancreas orthotopic portal vein injection immune-competent mice. Clinical relevance validated by digital spatial transcriptomic tumors. induces formation intraepithelial neoplasia (PanIN), these lesions also exhibit significant apoptotic signals. identified a subset ERKactiveDUSP2low continuing expand from early stage In vivo studies reveal that infiltrating macrophage-derived tissue inhibitor metallopeptidase 1 (TIMP-1) key factor maintaining population CD63-dependent manner. The further exacerbate macrophage-mediated malignancy, including loss trait, increased lymphangiogenesis, escape. Digital profiling samples demonstrates colocalization TIMP-1high macrophages CD63high cells. presence correlates with poor prognosis Our reveals vicious cycle between cells, providing mechanistic insight dynamic regulation directing progression.

Язык: Английский

Процитировано

1
Exosomal circular RNAs in tumor microenvironment: An emphasis on signaling pathways and clinical opportunities DOI Creative Commons
Junshu Li, Wencheng Zhou, Huiling Wang

и другие.

MedComm, Год журнала: 2024, Номер 5(12)

Опубликована: Ноя. 24, 2024

Exosomes can regulate the malignant progression of tumors by carrying a variety genetic information and transmitting it to target cells. Recent studies indicate that exosomal circular RNAs (circRNAs) multiple biological processes in carcinogenesis, such as tumor growth, metastasis, epithelial-mesenchymal transition, drug resistance, autophagy, metabolism, angiogenesis, immune escape. In microenvironment (TME), circRNAs be transferred among cells, endothelial cancer-associated fibroblasts, microbiota, affecting initiation progression. Due high stability widespread presence circRNAs, they hold promise biomarkers for diagnosis prognosis prediction blood urine. addition, designing nanoparticles targeting utilizing derived from cells or stem provide new strategies cancer therapy. this review, we examined crucial role regulating tumor-related signaling pathways summarized transmission between various types their impact on TME. Finally, our review highlights potential diagnostic prognostic biomarkers, well suggesting clinical

Язык: Английский

Процитировано

6
Unveiling the Promise: Navigating Clinical Trials 1978–2024 for PDAC DOI Open Access
A. Domínguez,

M Perz,

Yi Xu

и другие.

Cancers, Год журнала: 2024, Номер 16(21), С. 3564 - 3564

Опубликована: Окт. 23, 2024

Despite many decades of research, pancreatic ductal adenocarcinoma (PDAC) remains one the most difficult cancers to diagnose and treat effectively. Although there have been improvements in 5-year overall survival rate, it is still very low at 12.5%. The limited efficacy current therapies, even when PDAC detected early, underscores aggressive nature disease urgent need for more effective treatments. Clinical management relies heavily on a repertoire therapeutic interventions, highlighting significant gap between research efforts available Over 4300 clinical trials or are currently investigating different treatment modalities diagnostic strategies PDAC, including targeted immunotherapies, precision medicine approaches. These aim develop treatments improve early detection methods through advanced imaging techniques blood-based biomarkers. This review seeks categorize analyze PDAC-related across various dimensions understand why so few chemotherapeutic options patients despite numerous being conducted. aims provide comprehensive nuanced understanding landscape trials, with overarching goal identifying opportunities accelerate progress drug development patient outcomes fight against this devastating disease.

Язык: Английский

Процитировано

3
Targeting MXD1 sensitises pancreatic cancer to trametinib DOI
Shaoping Zhang, Shuang Deng, Ji Liu

и другие.

Gut, Год журнала: 2025, Номер unknown, С. gutjnl - 333408

Опубликована: Янв. 16, 2025

Background The resistance of pancreatic ductal adenocarcinoma (PDAC) to trametinib therapy limits its clinical use. However, the molecular mechanisms underlying in PDAC remain unclear. Objective We aimed illustrate and identify resistance-associated druggable targets, thus improving treatment efficacy trametinib-resistant PDAC. Design established patient-derived xenograft (PDX) models primary cell lines conduct functional experiments. also applied single-cell RNA sequencing, Assay for Transposase-accessible Chromatin with sequencing Cleavage Under Targets Tagmentation explore relevant mechanism. Results have identified a cancer subpopulation featured by hyperactivated viral mimicry response PDXs. demonstrated that PDXs induces expression transcription factor MAX dimerisation protein 1 (MXD1), which acts as cofactor histone methyltransferase mixed lineage leukaemia increased H3K4 trimethylation transposable element (TE) loci, enhancing chromatin accessibility TEs. Mechanistically, enhanced TEs produces excessive double-stranded RNAs, leading activation downstream oncogenic interferon-stimulated genes. Inhibiting MXD1 can recover drug vulnerability cells trametinib. Conclusions Our study has discovered an important mechanism target

Язык: Английский

Процитировано

0
Advancements in proteogenomics for preclinical targeted cancer therapy research DOI Creative Commons

Yuying Suo,

Yuanli Song, Yuqiu Wang

и другие.

Biophysics Reports, Год журнала: 2025, Номер 11(1), С. 56 - 56

Опубликована: Янв. 1, 2025

Advancements in molecular characterization technologies have accelerated targeted cancer therapy research at unprecedented resolution and dimensionality. Integrating comprehensive multi-omic profiling of a tumor, proteogenomics, marks transformative milestone for preclinical research. In this paper, we initially provided an overview proteogenomics research, spanning genomics, transcriptomics, proteomics. Subsequently, the applications were introduced examined from different perspectives, including but not limited to genetic alterations, quantifications, single-cell patterns, post-translational modification levels, subtype signatures, immune landscape. We also paid attention combined multi-omics data analysis pan-cancer analysis. This paper highlights crucial role elucidating mechanisms tumorigenesis, discovering effective therapeutic targets promising biomarkers, developing subtype-specific therapies.

Язык: Английский

Процитировано

0