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Nature Nov 2023Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies. Inflammatory and immunomodulatory signals co-exist in the pancreatic...
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with high resistance to therapies. Inflammatory and immunomodulatory signals co-exist in the pancreatic tumour microenvironment, leading to dysregulated repair and cytotoxic responses. Tumour-associated macrophages (TAMs) have key roles in PDAC, but their diversity has prevented therapeutic exploitation. Here we combined single-cell and spatial genomics with functional experiments to unravel macrophage functions in pancreatic cancer. We uncovered an inflammatory loop between tumour cells and interleukin-1β (IL-1β)-expressing TAMs, a subset of macrophages elicited by a local synergy between prostaglandin E (PGE) and tumour necrosis factor (TNF). Physical proximity with IL-1β TAMs was associated with inflammatory reprogramming and acquisition of pathogenic properties by a subset of PDAC cells. This occurrence was an early event in pancreatic tumorigenesis and led to persistent transcriptional changes associated with disease progression and poor outcomes for patients. Blocking PGE or IL-1β activity elicited TAM reprogramming and antagonized tumour cell-intrinsic and -extrinsic inflammation, leading to PDAC control in vivo. Targeting the PGE-IL-1β axis may enable preventive or therapeutic strategies for reprogramming of immune dynamics in pancreatic cancer.
Topics: Humans; Carcinogenesis; Carcinoma, Pancreatic Ductal; Dinoprostone; Disease Progression; Gene Expression Regulation, Neoplastic; Inflammation; Interleukin-1beta; Pancreatic Neoplasms; Tumor Microenvironment; Tumor Necrosis Factors; Tumor-Associated Macrophages
PubMed: 37914939
DOI: 10.1038/s41586-023-06685-2 -
Pancreatology : Official Journal of the... Mar 2024This study group aimed to revise the 2017 international consensus guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, and... (Review)
Review
This study group aimed to revise the 2017 international consensus guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) of the pancreas, and mainly focused on five topics; the revision of high-risk stigmata (HRS) and worrisome features (WF), surveillance of non-resected IPMN, surveillance after resection of IPMN, revision of pathological aspects, and investigation of molecular markers in cyst fluid. A new development from the prior guidelines is that systematic reviews were performed for each one of these topics, and published separately to provide evidence-based recommendations. One of the highlights of these new "evidence-based guidelines" is to propose a new management algorithm, and one major revision is to include into the assessment of HRS and WF the imaging findings from endoscopic ultrasound (EUS) and the results of cytological analysis from EUS-guided fine needle aspiration technique, when this is performed. Another key element of the current guidelines is to clarify whether lifetime surveillance for small IPMNs is required, and recommends two options, "stop surveillance" or "continue surveillance for possible development of concomitant pancreatic ductal adenocarcinoma", for small unchanged BD-IPMN after 5 years surveillance. Several other points are also discussed, including identifying high-risk features for recurrence in patients who underwent resection of non-invasive IPMN with negative surgical margin, summaries of the recent observations in the pathology of IPMN. In addition, the emerging role of cyst fluid markers that can aid in distinguishing IPMN from other pancreatic cysts and identify those IPMNs that harbor high-grade dysplasia or invasive carcinoma is discussed.
Topics: Humans; Pancreatic Intraductal Neoplasms; Pancreas; Pancreatic Neoplasms; Endosonography; Carcinoma, Pancreatic Ductal
PubMed: 38182527
DOI: 10.1016/j.pan.2023.12.009 -
Cellular and Molecular Life Sciences :... Jul 2023Pancreatic cancer is typically detected at an advanced stage, and is refractory to most forms of treatment, contributing to poor survival outcomes. The incidence of... (Review)
Review
Pancreatic cancer is typically detected at an advanced stage, and is refractory to most forms of treatment, contributing to poor survival outcomes. The incidence of pancreatic cancer is gradually increasing, linked to an aging population and increasing rates of obesity and pancreatitis, which are risk factors for this cancer. Sources of risk include adipokine signaling from fat cells throughout the body, elevated levels of intrapancreatic intrapancreatic adipocytes (IPAs), inflammatory signals arising from pancreas-infiltrating immune cells and a fibrotic environment induced by recurring cycles of pancreatic obstruction and acinar cell lysis. Once cancers become established, reorganization of pancreatic tissue typically excludes IPAs from the tumor microenvironment, which instead consists of cancer cells embedded in a specialized microenvironment derived from cancer-associated fibroblasts (CAFs). While cancer cell interactions with CAFs and immune cells have been the topic of much investigation, mechanistic studies of the source and function of IPAs in the pre-cancerous niche are much less developed. Intriguingly, an extensive review of studies addressing the accumulation and activity of IPAs in the pancreas reveals that unexpectedly diverse group of factors cause replacement of acinar tissue with IPAs, particularly in the mouse models that are essential tools for research into pancreatic cancer. Genes implicated in regulation of IPA accumulation include KRAS, MYC, TGF-β, periostin, HNF1, and regulators of ductal ciliation and ER stress, among others. These findings emphasize the importance of studying pancreas-damaging factors in the pre-cancerous environment, and have significant implications for the interpretation of data from mouse models for pancreatic cancer.
Topics: Mice; Animals; Pancreatic Neoplasms; Pancreatitis; Pancreas; Acinar Cells; Carcinoma, Pancreatic Ductal; Tumor Microenvironment
PubMed: 37452870
DOI: 10.1007/s00018-023-04855-z -
Nature Medicine Dec 2023Pancreatic ductal adenocarcinoma (PDAC), the most deadly solid malignancy, is typically detected late and at an inoperable stage. Early or incidental detection is...
Pancreatic ductal adenocarcinoma (PDAC), the most deadly solid malignancy, is typically detected late and at an inoperable stage. Early or incidental detection is associated with prolonged survival, but screening asymptomatic individuals for PDAC using a single test remains unfeasible due to the low prevalence and potential harms of false positives. Non-contrast computed tomography (CT), routinely performed for clinical indications, offers the potential for large-scale screening, however, identification of PDAC using non-contrast CT has long been considered impossible. Here, we develop a deep learning approach, pancreatic cancer detection with artificial intelligence (PANDA), that can detect and classify pancreatic lesions with high accuracy via non-contrast CT. PANDA is trained on a dataset of 3,208 patients from a single center. PANDA achieves an area under the receiver operating characteristic curve (AUC) of 0.986-0.996 for lesion detection in a multicenter validation involving 6,239 patients across 10 centers, outperforms the mean radiologist performance by 34.1% in sensitivity and 6.3% in specificity for PDAC identification, and achieves a sensitivity of 92.9% and specificity of 99.9% for lesion detection in a real-world multi-scenario validation consisting of 20,530 consecutive patients. Notably, PANDA utilized with non-contrast CT shows non-inferiority to radiology reports (using contrast-enhanced CT) in the differentiation of common pancreatic lesion subtypes. PANDA could potentially serve as a new tool for large-scale pancreatic cancer screening.
Topics: Humans; Artificial Intelligence; Deep Learning; Pancreatic Neoplasms; Tomography, X-Ray Computed; Pancreas; Carcinoma, Pancreatic Ductal; Retrospective Studies
PubMed: 37985692
DOI: 10.1038/s41591-023-02640-w -
Gastroenterology Oct 2023As pancreatic ductal adenocarcinoma (PDAC) continues to be recalcitrant to therapeutic interventions, including poor response to immunotherapy, albeit effective in other... (Meta-Analysis)
Meta-Analysis
BACKGROUND & AIMS
As pancreatic ductal adenocarcinoma (PDAC) continues to be recalcitrant to therapeutic interventions, including poor response to immunotherapy, albeit effective in other solid malignancies, a more nuanced understanding of the immune microenvironment in PDAC is urgently needed. We aimed to unveil a detailed view of the immune micromilieu in PDAC using a spatially resolved multimodal single-cell approach.
METHODS
We applied single-cell RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry, and mass cytometry to profile the immune compartment in treatment-naïve PDAC tumors and matched adjacent normal pancreatic tissue, as well as in the systemic circulation. We determined prognostic associations of immune signatures and performed a meta-analysis of the immune microenvironment in PDAC and lung adenocarcinoma on single-cell level.
RESULTS
We provided a spatially resolved fine map of the immune landscape in PDAC. We substantiated the exhausted phenotype of CD8 T cells and immunosuppressive features of myeloid cells, and highlighted immune subsets with potentially underappreciated roles in PDAC that diverged from immune populations within adjacent normal areas, particularly CD4 T cell subsets and natural killer T cells that are terminally exhausted and acquire a regulatory phenotype. Differential analysis of immune phenotypes in PDAC and lung adenocarcinoma revealed the presence of extraordinarily immunosuppressive subtypes in PDAC, along with a distinctive immune checkpoint composition.
CONCLUSIONS
Our study sheds light on the multilayered immune dysfunction in PDAC and presents a holistic view of the immune landscape in PDAC and lung adenocarcinoma, providing a comprehensive resource for functional studies and the exploration of therapeutically actionable targets in PDAC.
Topics: Humans; Multiomics; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Immune System Diseases; Adenocarcinoma of Lung; Single-Cell Analysis; Tumor Microenvironment
PubMed: 37263303
DOI: 10.1053/j.gastro.2023.05.036 -
Cancer Cell Jan 2024Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Cancer-associated fibroblasts (CAFs) are recognized potential therapeutic targets, but poor understanding...
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Cancer-associated fibroblasts (CAFs) are recognized potential therapeutic targets, but poor understanding of these heterogeneous cell populations has limited the development of effective treatment strategies. We previously identified transforming growth factor beta (TGF-β) as a main driver of myofibroblastic CAFs (myCAFs). Here, we show that epidermal growth factor receptor/Erb-B2 receptor (EGFR/ERBB2) signaling is induced by TGF-β in myCAFs through an autocrine process mediated by amphiregulin. Inhibition of this EGFR/ERBB2-signaling network in PDAC organoid-derived cultures and mouse models differentially impacts distinct CAF subtypes, providing insights into mechanisms underpinning their heterogeneity. Remarkably, EGFR-activated myCAFs promote PDAC metastasis in mice, unmasking functional significance in myCAF heterogeneity. Finally, analyses of other cancer datasets suggest that these processes might operate in other malignancies. These data provide functional relevance to myCAF heterogeneity and identify a candidate target for preventing tumor invasion in PDAC.
Topics: Mice; Animals; Myofibroblasts; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Signal Transduction; Transforming Growth Factor beta; Tumor Microenvironment
PubMed: 38157863
DOI: 10.1016/j.ccell.2023.12.002 -
International Journal of Nanomedicine 2023Pancreatic cancer is a highly malignant and incurable disease, characterized by its aggressive nature and high fatality rate. The most common type is pancreatic ductal... (Review)
Review
Pancreatic cancer is a highly malignant and incurable disease, characterized by its aggressive nature and high fatality rate. The most common type is pancreatic ductal adenocarcinoma (PDAC), which has poor prognosis and high mortality rate. Current treatments for pancreatic cancer mainly encompass surgery, chemotherapy, radiotherapy, targeted therapy, and combination regimens. However, despite efforts to improve prognosis, and the 5-year survival rate for pancreatic cancer remains very low. Therefore, it's urgent to explore novel therapeutic approaches. With the rapid development of therapeutic strategies in recent years, new ideas have been provided for treating pancreatic cancer. This review expositions the advancements in nano drug delivery system, molecular targeted drugs, and photo-thermal treatment combined with nanotechnology for pancreatic cancer. It comprehensively analyzes the prospects of combined drug delivery strategies for treating pancreatic cancer, aiming at a deeper understanding of the existing drugs and therapeutic approaches, promoting the development of new therapeutic drugs, and attempting to enhance the therapeutic effect for patients with this disease.
Topics: Humans; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Drug Delivery Systems; Nanotechnology
PubMed: 37489138
DOI: 10.2147/IJN.S413496 -
Cancer Research Sep 2023Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been...
UNLABELLED
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 antitumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.
SIGNIFICANCE
KRAS-mutant pancreatic cancer models, including KRAS inhibitor-resistant models, show exquisite sensitivity to combined pan-ERBB and KRAS targeting, which provides the rationale for testing this drug combination in clinical trials.
Topics: Mice; Animals; Afatinib; ErbB Receptors; Proto-Oncogene Proteins p21(ras); Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Mutation; Cell Line, Tumor
PubMed: 37378556
DOI: 10.1158/0008-5472.CAN-23-1313 -
Nature Communications Aug 2023Bulk analyses of pancreatic ductal adenocarcinoma (PDAC) samples are complicated by the tumor microenvironment (TME), i.e. signals from fibroblasts, endocrine, exocrine,...
Bulk analyses of pancreatic ductal adenocarcinoma (PDAC) samples are complicated by the tumor microenvironment (TME), i.e. signals from fibroblasts, endocrine, exocrine, and immune cells. Despite this, we and others have established tumor and stroma subtypes with prognostic significance. However, understanding of underlying signals driving distinct immune and stromal landscapes is still incomplete. Here we integrate 92 single cell RNA-seq samples from seven independent studies to build a reproducible PDAC atlas with a focus on tumor-TME interdependence. Patients with activated stroma are synonymous with higher myofibroblastic and immunogenic fibroblasts, and furthermore show increased M2-like macrophages and regulatory T-cells. Contrastingly, patients with 'normal' stroma show M1-like recruitment, elevated effector and exhausted T-cells. To aid interoperability of future studies, we provide a pretrained cell type classifier and an atlas of subtype-based signaling factors that we also validate in mouse data. Ultimately, this work leverages the heterogeneity among single-cell studies to create a comprehensive view of the orchestra of signaling interactions governing PDAC.
Topics: Animals; Mice; Tumor Microenvironment; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Fibroblasts
PubMed: 37633924
DOI: 10.1038/s41467-023-40895-6 -
Nature Communications Jun 2023Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best...
Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best available systemic treatment. However, the discovery of safe and available adjuncts to enhance chemotherapeutic efficacy can still improve survival outcomes. We show that a hyperglycemic state substantially enhances the efficacy of conventional single- and multi-agent chemotherapy regimens against PDAC. Molecular analyses of tumors exposed to high glucose levels reveal that the expression of GCLC (glutamate-cysteine ligase catalytic subunit), a key component of glutathione biosynthesis, is diminished, which in turn augments oxidative anti-tumor damage by chemotherapy. Inhibition of GCLC phenocopies the suppressive effect of forced hyperglycemia in mouse models of PDAC, while rescuing this pathway mitigates anti-tumor effects observed with chemotherapy and high glucose.
Topics: Animals; Mice; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Administration, Cutaneous; Glucose
PubMed: 37380658
DOI: 10.1038/s41467-023-38921-8