IL-1β+ macrophages fuel pathogenic inflammation in pancreatic cancer

Nature, Год журнала: 2023, Номер 623(7986), С. 415 - 422

Опубликована: Ноя. 1, 2023

Язык: Английский

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Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Май 6, 2024

Abstract Background Metabolic reprogramming and epigenetic alterations contribute to the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). Lactate-dependent histone modification is a new type mark, which links glycolysis metabolite process lactylation. However, role lactylation in PDAC remains unclear. Methods The level was identified by western blot immunohistochemistry, its relationship with overall survival evaluated using Kaplan-Meier plot. participation growth progression confirmed through inhibition inhibitors or lactate dehydrogenase A ( LDHA ) knockdown both vitro vivo. potential writers erasers were functional experiments. target genes H3K18 (H3K18la) screened CUT&Tag RNA-seq analyses. candidate TTK protein kinase BUB1 mitotic checkpoint serine/threonine B BUB1B validated ChIP-qPCR, RT-qPCR Next, effects these two overexpression. interaction between Co-IP assay. Results Histone lactylation, especially H3K18la elevated PDAC, high associated poor prognosis. suppression glycolytic activity different kinds contributed anti-tumor E1A binding p300 (P300) deacetylase 2 writer eraser cells, respectively. enriched at promoters activated transcription regulators . Interestingly, could elevate expression P300 turn increased glycolysis. Moreover, phosphorylated tyrosine 239 (Y239) LDHA, subsequently upregulated levels. Conclusions glycolysis-H3K18la-TTK/BUB1B positive feedback loop exacerbates dysfunction PDAC. These findings delivered exploration significant inter-relationship metabolic regulation, might pave way toward novel treatment strategies therapy.

Язык: Английский

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Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma

npj Precision Oncology, Год журнала: 2024, Номер 8(1)

Опубликована: Фев. 3, 2024

Abstract The relevance of KRAS mutation alleles to clinical outcome remains inconclusive in pancreatic adenocarcinoma (PDAC). We conducted a retrospective study 803 patients with PDAC (42% metastatic disease) at MD Anderson Cancer Center. Overall survival (OS) analysis demonstrated that status and subtypes were prognostic ( p < 0.001). Relative wildtype tumors (median OS 38 months), G12R had similar 34 while Q61 G12D mutated shorter 20 months [HR: 1.9, 95% CI 1.2–3.0, = 0.006] 22 1.7, 1.3–2.3, 0.001], respectively). There was enrichment (34% vs 24%, OR: 1.2–2.4, 0.001) well moderately differentiated (14% 9%, 1.05–2.99, 0.04). Similar findings observed the external validation cohort (PanCAN’s Know Your Tumor® dataset, n 408).

Язык: Английский

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Liquid biopsy in cancer current: status, challenges and future prospects

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Дек. 1, 2024

Cancer has a high mortality rate across the globe, and tissue biopsy remains gold standard for tumor diagnosis due to its level of laboratory standardization, good consistency results, relatively stable samples, accuracy results. However, there are still many limitations drawbacks in application tumor. The emergence liquid provides new ideas early prognosis Compared with biopsy, advantages treatment various types cancer, including non-invasive, quickly so on. Currently, detection received widely attention. It is now undergoing rapid progress, it holds significant potential future applications. Around now, biopsies encompass several components such as circulating cells, DNA, exosomes, microRNA, RNA, platelets, endothelial cells. In addition, advances identification indicators have significantly enhanced possibility utilizing clinical settings. this review, we will discuss application, challenges some common tumors from perspective diverse systems tumors, look forward development prospects field cancer treatment.

Язык: Английский

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Mapping functional to morphological variation reveals the basis of regional extracellular matrix subversion and nerve invasion in pancreatic cancer

Cancer Cell, Год журнала: 2024, Номер 42(4), С. 662 - 681.e10

Опубликована: Март 21, 2024

Язык: Английский

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Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)

Опубликована: Май 22, 2024

Abstract Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance toxicity still remain. Due the advancement of immuno-oncology, an increasing number novel immunoregulatory targets mechanisms are being revealed, with relevant therapies promising improve clinical immunotherapy in foreseeable future. Therefore, comprehending larger picture is important. In this review, we analyze summarize current landscape preclinical translational mechanistic research, drug development, trials that brought about next-generation pharmacological anti-cancer agents candidates beyond classical immune checkpoint inhibitors. Along further clarification immunobiology advances antibody engineering, targeting additional inhibitory checkpoints, including LAG-3, TIM-3, TIGIT, CD47, B7 family members becoming important part research discovery, as structurally functionally optimized agonists co-stimulatory molecules T cells. Exemplified bispecific cell engagers, newly emerging bi-specific multi-specific antibodies can provide considerable benefits. Next-generation also include epigenetic drugs cytokine-based therapeutics. Cell therapies, vaccines, oncolytic viruses not covered review. This comprehensive review might aid development fastest possible adoption effective immuno-oncology modalities for benefit patients.

Язык: Английский

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Schwann cells in pancreatic cancer: Unraveling their multifaceted roles in tumorigenesis and neural interactions

Cancer Letters, Год журнала: 2024, Номер 587, С. 216689 - 216689

Опубликована: Фев. 15, 2024

Язык: Английский

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Molecular mechanisms of pancreatic cancer liver metastasis: the role of PAK2

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Янв. 26, 2024

Background Pancreatic cancer remains an extremely malignant digestive tract tumor, posing a significant global public health burden. Patients with pancreatic cancer, once metastasis occurs, lose all hope of cure, and prognosis is poor. It important to investigate liver in depth, not just because it the most common form but also crucial for treatment planning assessment. This study aims delve into mechanisms metastasis, goal providing scientific groundwork development future methods drugs. Methods We explored using single-cell sequencing data (GSE155698 GSE154778) bulk (GSE71729, GSE19279, TCGA-PAAD). Initially, Seurat package was employed processing obtain expression matrices primary lesions metastatic lesions. Subsequently, high-dimensional weighted gene co-expression network analysis (hdWGCNA) used identify genes associated metastasis. Machine learning algorithms COX regression models were further screen related patient prognosis. Informed by both biological understanding outcomes algorithms, we meticulously identified ultimate set metastasis-related (LRG). In LRG genes, various databases utilized validate their association order analyze effects these agents on tumor microenvironment, conducted in-depth analysis, including changes signaling pathways (GSVA), cell differentiation (pseudo-temporal analysis), communication networks (cell downstream transcription factors (transcription factor activity prediction). Additionally, drug sensitivity metabolic performed reveal gemcitabine resistance pathways. Finally, functional experiments silencing PANC-1 Bx-PC-3 cells its influence proliferation invasiveness cells. Results Through series algorithmic filters, PAK2 as key promoting GSVA elucidated activation TGF-beta pathway promote occurrence Pseudo-temporal revealed correlation between lower status Cell that overexpression promotes microenvironment. Transcription prediction displayed regulated PAK2. Drug impact CCK8 showed led decrease proliferative capacity scratch demonstrated low decreased invasion capability Flow cytometry reveals significantly inhibited apoptosis lines. Molecules inhibition PAK2, there corresponding molecules EMT. Conclusion facilitated angiogenic potential epithelial-mesenchymal transition process activating pathway. Simultaneously, level cells, consequently enhancing malignancy. fostered augments chemoresistance, modulates energy metabolism summary, emerged pivotal orchestrating Intervening may offer promising therapeutic strategy preventing improving

Язык: Английский

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From Machine Learning to Patient Outcomes: A Comprehensive Review of AI in Pancreatic Cancer

Diagnostics, Год журнала: 2024, Номер 14(2), С. 174 - 174

Опубликована: Янв. 12, 2024

Pancreatic cancer is a highly aggressive and difficult-to-detect with poor prognosis. Late diagnosis common due to lack of early symptoms, specific markers, the challenging location pancreas. Imaging technologies have improved diagnosis, but there still room for improvement in standardizing guidelines. Biopsies histopathological analysis are tumor heterogeneity. Artificial Intelligence (AI) revolutionizes healthcare by improving treatment, patient care. AI algorithms can analyze medical images precision, aiding disease detection. also plays role personalized medicine analyzing data tailor treatment plans. It streamlines administrative tasks, such as coding documentation, provides assistance through chatbots. However, challenges include privacy, security, ethical considerations. This review article focuses on potential transforming pancreatic care, offering diagnostics, treatments, operational efficiency, leading better outcomes.

Язык: Английский

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Lactate and lactylation in cancer

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Фев. 11, 2025

Abstract Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation fate regulation in physiological pathological settings, particularly intricate conditions such as cancer. Specifically, been demonstrated to be pivotal molding tumor microenvironment (TME) through its effects different cell populations. Within cells, impacts signaling pathways, augments shuttle process, boosts resistance oxidative stress, contributes lactylation. In various populations, interplay between immune cells governs processes differentiation, response, surveillance, treatment effectiveness. Furthermore, communication stromal/endothelial supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, drug resistance. Focusing production transport, specifically dehydrogenase (LDH) monocarboxylate transporters (MCT), shown promise Inhibitors targeting LDH MCT act both suppressors enhancers immunotherapy, leading a synergistic therapeutic effect when combined with immunotherapy. The review underscores importance progression provides valuable perspectives potential approaches that target vulnerability metabolism, highlighting Heel Achilles for cancer treatment.

Язык: Английский

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