A Classical Epithelial State Drives Acute Resistance to KRAS Inhibition in Pancreatic Cancer

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

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Progressive lung fibrosis: reprogramming a genetically vulnerable bronchoalveolar epithelium

Journal of Clinical Investigation, Год журнала: 2025, Номер 135(1)

Опубликована: Янв. 1, 2025

Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: first establishes a vulnerable bronchoalveolar epithelium, second triggers mechanisms reprogram distal epithelia to initiate perpetuate profibrotic phenotype. While vulnerability most often driven by common or rare variants, subsequent injury results in persistent changes cell biology disrupt tissue homeostasis activate fibroblasts. The dynamic can best be contextualized temporally, including stages vulnerability, early disease, progressive lung fibrosis. These dimensions highlight critical adversely epithelial function, fibroblasts, lead remodeling. Together better recognition conceptual approach should novel therapeutics directed at etiologic temporal drivers will ultimately transform care patients from palliative curative.

Язык: Английский

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Glucocorticoid receptor suppresses GATA6-mediated RNA polymerase II pause release to modulate classical subtype identity in pancreatic cancer

Gut, Год журнала: 2025, Номер unknown, С. gutjnl - 334374

Опубликована: Янв. 30, 2025

Background Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with 5-year survival rate of 12%. It has two major molecular subtypes: classical and basal, regulated by the master transcription factors (MTFs) GATA6 ΔNp63, respectively. Objective This study sought to uncover transcriptional regulatory mechanisms controlling PDAC subtype identity. Design We integrated primary tumour single-cell RNA-seq, patient-derived xenograft RNA-seq multispectral imaging identify MTF-dependent, subtype-specific markers. created fluorescent reporter systems conducted drug screenings find actionable targets. analysed chromatin accessibility (ATAC-seq), genome-wide occupancy (ChIP-seq) for epigenetic status (H3K27ac), MTFs (GATA6, ΔNp63), RNA polymerase II (Pol II), H3K4me3-anchored topology (HiChIP) nascent capture sequencing (PRO-seq). Additionally, we used nuclease-dead Cas9 (dCas9) manipulate mechanisms. Results Our approach identified glucocorticoid receptor (GR) agonists as agents that suppress programme interacting GATA6. regulates classical-specific through promoter-proximal pause release. Depletion increased Pol at GATA6-bound enhancers start sites, stabilising enhancer–promoter interactions. Artificially inducing pausing dCas9 abrogated target gene expression induced both enhancer promoter. Conversely, in basal ΔNp63 promotes recruitment stabilises Conclusion provides new insights into control role GR

Язык: Английский

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Spatial heterogeneity of immune regulators drives dynamic changes of local immune responses, affecting disease outcomes in pancreatic cancer

Clinical Cancer Research, Год журнала: 2024, Номер 30(18), С. 4215 - 4226

Опубликована: Июль 15, 2024

Pancreatic ductal adenocarcinoma (PDAC) is considered a low-immunogenic (LI) tumor with "cold" microenvironment and mostly unresponsive to immune checkpoint blockade therapies. In this study, we decipher the impact of intratumoral heterogeneity determinants on antitumor responses.

Язык: Английский

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Disrupting AGR2/IGF1 paracrine and reciprocal signaling for pancreatic cancer therapy

Cell Reports Medicine, Год журнала: 2025, Номер unknown, С. 101927 - 101927

Опубликована: Фев. 1, 2025

Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive and characterized by pronounced desmoplasia. PDAC cells communicate with cancer-associated fibroblasts (CAFs) in a paracrine/reciprocal manner, substantially promoting tumor growth desmoplastic responses. This study highlights the critical role of anterior gradient 2 (AGR2), an endoplasmic reticulum protein disulfide isomerase, secreted to activate CAFs via Wnt signaling pathway. Activated CAFs, turn, secrete insulin-like factor 1 (IGF1), which enhances AGR2 expression secretion through IGF1 receptor (IGF1R)/c-JUN axis. Within cells, acts as thioredoxin, aiding folding cell surface presentation IGF1R, essential for PDAC's response CAF-derived IGF1. reciprocal AGR2/IGF1 loop intensifies desmoplasia, immunosuppression, tumorigenesis, creating harmful feedback loop. Targeting both pathways disrupts this interaction, reduces restores anti-tumor immunity preclinical models, offering promising therapeutic strategy against PDAC.

Язык: Английский

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Pancreatic cancer subtyping - the keystone of precision treatment

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Апрель 8, 2025

In recent years, the incidence and mortality rates of pancreatic cancer have been rising, posing a severe threat to human health. Tumor heterogeneity remains critical barrier advancing diagnosis treatment efforts. The lack specific early symptoms, limited diagnostic methods, high biological complexity, restricted therapeutic options contribute poor outcomes prognosis cancer. Therefore, there is an urgent need explore different subtypes in-depth develop personalized strategies tailored each subtype. Increasing evidence highlights pivotal role molecular subtyping in treating This review focuses on advancements classifying approaches, discussed from perspectives gene mutations, genomics, transcriptomics, proteomics, metabolomics, immunomics.

Язык: Английский

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Road Map to Defeat Pancreatic Cancer

Annual Review of Cancer Biology, Год журнала: 2025, Номер 9(1), С. 1 - 20

Опубликована: Апрель 11, 2025

Pancreatic cancer is a notoriously deadly disease characterized by many challenges in clinical management. Despite important advances our understanding of pancreatic progression and its underlying molecular biology over the last decades, there long road ahead if we aim to meaningfully improve patient outcomes this difficult disease. Treatment options remain limited, prognosis, although improving, remains bleak. As build toward future, propose framework for targeting seven hallmarks an effort cure The high mortality aggressive nature can be largely ascribed ( ) diagnostic deficiencies, b chronic inflammation, c desmoplastic stroma, d early metastasis, e KRAS signaling, f metabolism, g rapid deconditioning. Here, outline presented each these highlight ongoing research tackle one.

Язык: Английский

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Single‐Cell Profiling Reveals Conserved Differentiation and Partial EMT Programs Orchestrating Ecosystem‐Level Antagonisms in Head and Neck Cancer

Journal of Cellular and Molecular Medicine, Год журнала: 2025, Номер 29(9)

Опубликована: Май 1, 2025

ABSTRACT Head and neck squamous cell carcinoma (HNSC) exhibits profound intratumoral heterogeneity, driven by dynamic interactions between malignant cells the tumour microenvironment (TME). Using consensus non‐negative matrix factorisation (cNMF) on multi‐site HNSC single‐cell transcriptomes, we resolving conserved meta‐programs define cellular ecosystems. Six major epithelial programmes emerged, including a differentiation‐associated programme (Epi_Diff) correlated with SPDEF activity favourable patient prognosis, an invasive (Epi_pEMT) potentially controlled TEAD4‐mediated ECM remodelling, exhibiting partial EMT markers (VIM, TGFB1). Compartment‐specific crosstalk analysis revealed Epi_pEMT may coordinate mCAF1 fibroblasts TAM(SPP1) through COL1A1‐CD44 SPP1‐CD44 signalling, suggesting potential formation of pro‐invasive niche. Conversely, Epi_Diff interact NK/T CEACAM5‐CD8A CCL5‐ACKR2, contribute to inhibit immune infiltration. Multi‐compartment correlation three ecosystem‐level patterns: (1) Inverse association (Spearman R = −0.43); (2) Negative abundance cCAF frequency ( −0.48); (3) dominance inversely correlating both TAM(C1Q) −0.43) infiltration −0.36). These axes suggest hierarchical ecology framework where lineage‐specific polarisation inter‐compartment synergies collectively govern disease progression.

Язык: Английский

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AGR2: The Covert Driver and New Dawn of Hepatobiliary and Pancreatic Cancer Treatment

Biomolecules, Год журнала: 2024, Номер 14(7), С. 743 - 743

Опубликована: Июнь 23, 2024

The anterior gradient protein 2 (AGR2) plays a crucial role in facilitating the formation of disulfide bonds within endoplasmic reticulum (ER). Research suggests that AGR2 can function as an oncogene, with its heightened expression linked to advancement hepatobiliary and pancreatic cancers through invasion metastasis. Notably, not only serves pro-oncogenic agent but also downstream targeting protein, indirectly fostering cancer progression. This comprehensive review delves into established functions patterns AGR2, emphasizing pivotal progression, particularly malignancies. Furthermore, emerges potential prognostic marker promising target for immunotherapy, offering novel avenues treatment enhancing patient outcomes.

Язык: Английский

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Oncogenic GNAS drives a gastric pylorus program in intraductal papillary mucinous neoplasms of the pancreas

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 28, 2024

ABSTRACT OBJECTIVE Intraductal Papillary Mucinous Neoplasms (IPMNs) are cystic lesions and bona fide precursors for pancreatic ductal adenocarcinoma (PDAC). Recently, we showed that acinar to metaplasia, an injury repair program, is characterized by a transcriptomic program similar gastric spasmolytic polypeptide expressing metaplasia (SPEM), suggesting common mechanisms of reprogramming between the stomach pancreas. The aims this study were assay IPMN pyloric markers identify molecular drivers program. DESIGN We analyzed RNA-seq studies markers, which validated immunostaining in patient samples. Cell lines Kras G12D +/− GNAS R201C manipulated distinct overlapping programs driven each oncogene. A PyScenic-based regulon analysis was performed Expression candidate evaluated immunostaining. RESULTS Pyloric identified human IPMN. drove expression these cell siRNA targeting or demonstrates amplifies mucinous, phenotype. Regulon role transcription factors SPDEF, CREB3L1, CREB3L4, expressed siRNA-targeting Spdef inhibited mucin production. CONCLUSION De novo SPEM phenotype has been pancreatitis -driven PanIN ;GNAS IPMN, stomach. transition from may reflect disease progression and/or oncogenic mutation. IPMN-specific mucinous phenotype, part, through SPDEF.

Язык: Английский

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