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Molecular Cancer Jul 2023Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared to the localized... (Review)
Review
Immunosuppression is a hallmark of pancreatic ductal adenocarcinoma (PDAC), contributing to early metastasis and poor patient survival. Compared to the localized tumors, current standard-of-care therapies have failed to improve the survival of patients with metastatic PDAC, that necessecitates exploration of novel therapeutic approaches. While immunotherapies such as immune checkpoint blockade (ICB) and therapeutic vaccines have emerged as promising treatment modalities in certain cancers, limited responses have been achieved in PDAC. Therefore, specific mechanisms regulating the poor response to immunotherapy must be explored. The immunosuppressive microenvironment driven by oncogenic mutations, tumor secretome, non-coding RNAs, and tumor microbiome persists throughout PDAC progression, allowing neoplastic cells to grow locally and metastasize distantly. The metastatic cells escaping the host immune surveillance are unique in molecular, immunological, and metabolic characteristics. Following chemokine and exosomal guidance, these cells metastasize to the organ-specific pre-metastatic niches (PMNs) constituted by local resident cells, stromal fibroblasts, and suppressive immune cells, such as the metastasis-associated macrophages, neutrophils, and myeloid-derived suppressor cells. The metastatic immune microenvironment differs from primary tumors in stromal and immune cell composition, functionality, and metabolism. Thus far, multiple molecular and metabolic pathways, distinct from primary tumors, have been identified that dampen immune effector functions, confounding the immunotherapy response in metastatic PDAC. This review describes major immunoregulatory pathways that contribute to the metastatic progression and limit immunotherapy outcomes in PDAC. Overall, we highlight the therapeutic vulnerabilities attributable to immunosuppressive factors and discuss whether targeting these molecular and immunological "hot spots" could improve the outcomes of PDAC immunotherapies.
Topics: Humans; Immunosuppression Therapy; Pancreatic Neoplasms; Adenocarcinoma; Immunotherapy; Carcinoma, Pancreatic Ductal; Tumor Microenvironment
PubMed: 37488598
DOI: 10.1186/s12943-023-01813-y -
Signal Transduction and Targeted Therapy Jul 2023VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can...
VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways, thereby conferring resistance to VEGF inhibitors. Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD. The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth, and worse prognosis. In cells and mice with xenograft tumors, BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner. Mechanistically, as an RNA binding protein, BICC1 bounds to the 3'UTR of Lipocalin-2 (LCN2) mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells. When its level is elevated, LCN2 binds to its receptor 24p3R, which directly phosphorylates JAK2 and activates JAK2/STAT3 signal, leading to increased production of an angiogenic factor CXCL1. Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice, and increased the tumor suppressive effect of gemcitabine. In conclusion, BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer, leading to resistance to VEGF inhibitors. BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.
Topics: Humans; Animals; Mice; Pancreatic Neoplasms; Vascular Endothelial Growth Factor A; Adenocarcinoma; RNA-Binding Proteins
PubMed: 37443111
DOI: 10.1038/s41392-023-01478-5 -
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 -
Genes & Development Sep 2023Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial...
Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial antitumor activity followed by recurrence due to cancer cell-intrinsic and immune-mediated paracrine mechanisms. Here, we explored the potential role of cancer-associated fibroblasts (CAFs) in enabling KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2 and ERBB3 receptor tyrosine kinases as a mechanism by which KRAS*-independent growth is supported. Genetic extinction or pharmacological inhibition of KRAS* resulted in up-regulation of ERBB2 and ERBB3 expression in human and murine models, which prompted cancer cell utilization of CAF-derived NRG1 as a survival factor. Genetic depletion or pharmacological inhibition of ERBB2/3 or NRG1 abolished KRAS* bypass and synergized with KRAS inhibitors in combination treatments in mouse and human PDAC models. Thus, we found that CAFs can contribute to KRAS* inhibitor therapy resistance via paracrine mechanisms, providing an actionable therapeutic strategy to improve the effectiveness of KRAS* inhibitors in PDAC patients.
Topics: Humans; Animals; Mice; Proto-Oncogene Proteins p21(ras); Cell Proliferation; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Neuregulin-1
PubMed: 37775182
DOI: 10.1101/gad.351037.123 -
Cancer Discovery Aug 2023Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most common subtype of...
Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential.
UNLABELLED
Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most common subtype of IPMNs harbors a gastric foveolar-type epithelium, and these low-grade mucinous neoplasms are harbingers of IPMNs with high-grade dysplasia and cancer. The molecular underpinning of gastric differentiation in IPMNs is unknown, although identifying drivers of this indolent phenotype might enable opportunities for intercepting progression to high-grade IPMN and cancer. We conducted spatial transcriptomics on a cohort of IPMNs, followed by orthogonal and cross-species validation studies, which established the transcription factor NKX6-2 as a key determinant of gastric cell identity in low-grade IPMNs. Loss of NKX6-2 expression is a consistent feature of IPMN progression, while reexpression of Nkx6-2 in murine IPMN lines recapitulates the aforementioned gastric transcriptional program and glandular morphology. Our study identifies NKX6-2 as a previously unknown transcription factor driving indolent gastric differentiation in IPMN pathogenesis.
SIGNIFICANCE
Identification of the molecular features driving IPMN development and differentiation is critical to prevent cancer progression and enhance risk stratification. We used spatial profiling to characterize the epithelium and microenvironment of IPMN, which revealed a previously unknown link between NKX6-2 and gastric differentiation, the latter associated with indolent biological potential. See related commentary by Ben-Shmuel and Scherz-Shouval, p. 1768. This article is highlighted in the In This Issue feature, p. 1749.
Topics: Animals; Mice; Carcinoma, Pancreatic Ductal; Cell Differentiation; Neoplasms, Cystic, Mucinous, and Serous; Pancreas; Pancreatic Intraductal Neoplasms; Pancreatic Neoplasms; Transcriptome; Tumor Microenvironment
PubMed: 37285225
DOI: 10.1158/2159-8290.CD-22-1200 -
Cell Reports. Medicine Feb 2024Prior observational studies suggest an association between intra-pancreatic fat deposition (IPFD) and pancreatic ductal adenocarcinoma (PDAC); however, the causal... (Observational Study)
Observational Study
Prior observational studies suggest an association between intra-pancreatic fat deposition (IPFD) and pancreatic ductal adenocarcinoma (PDAC); however, the causal relationship is unclear. To elucidate causality, we conduct a prospective observational study using magnetic resonance imaging (MRI)-measured IPFD data and also perform a Mendelian randomization study using genetic instruments for IPFD. In the observational study, we use UK Biobank data (N = 29,463, median follow-up: 4.5 years) and find that high IPFD (>10%) is associated with PDAC risk (adjusted hazard ratio [HR]: 3.35, 95% confidence interval [95% CI]: 1.60-7.00). In the Mendelian randomization study, we leverage eight out of nine IPFD-associated genetic variants (p < 5 × 10) from a genome-wide association study in the UK Biobank (N = 25,617) and find that genetically determined IPFD is associated with PDAC (odds ratio [OR] per 1-standard deviation [SD] increase in IPFD: 2.46, 95% CI: 1.38-4.40) in the Pancreatic Cancer Cohort Consortium I, II, III (PanScan I-III)/Pancreatic Cancer Case-Control Consortium (PanC4) dataset (8,275 PDAC cases and 6,723 non-cases). This study provides evidence for a potential causal role of IPFD in the pathogenesis of PDAC. Thus, reducing IPFD may lower PDAC risk.
Topics: Humans; Genome-Wide Association Study; Mendelian Randomization Analysis; Prospective Studies; Pancreas; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal
PubMed: 38280379
DOI: 10.1016/j.xcrm.2023.101391 -
Gut Nov 2023Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Differentiation from chronic pancreatitis (CP) is currently inaccurate in about one-third of cases....
OBJECTIVE
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Differentiation from chronic pancreatitis (CP) is currently inaccurate in about one-third of cases. Misdiagnoses in both directions, however, have severe consequences for patients. We set out to identify molecular markers for a clear distinction between PDAC and CP.
DESIGN
Genome-wide variations of DNA-methylation, messenger RNA and microRNA level as well as combinations thereof were analysed in 345 tissue samples for marker identification. To improve diagnostic performance, we established a random-forest machine-learning approach. Results were validated on another 48 samples and further corroborated in 16 liquid biopsy samples.
RESULTS
Machine-learning succeeded in defining markers to differentiate between patients with PDAC and CP, while low-dimensional embedding and cluster analysis failed to do so. DNA-methylation yielded the best diagnostic accuracy by far, dwarfing the importance of transcript levels. Identified changes were confirmed with data taken from public repositories and validated in independent sample sets. A signature of six DNA-methylation sites in a CpG-island of the protein kinase C beta type gene achieved a validated diagnostic accuracy of 100% in tissue and in circulating free DNA isolated from patient plasma.
CONCLUSION
The success of machine-learning to identify an effective marker signature documents the power of this approach. The high diagnostic accuracy of discriminating PDAC from CP could have tremendous consequences for treatment success, once the result from still a limited number of liquid biopsy samples would be confirmed in a larger cohort of patients with suspected pancreatic cancer.
Topics: Humans; Pancreatic Neoplasms; Pancreatitis, Chronic; Carcinoma, Pancreatic Ductal; DNA Methylation; DNA; Biomarkers, Tumor
PubMed: 37709492
DOI: 10.1136/gutjnl-2023-330155 -
Nature Aug 2023A growing body of literature suggests that alterations in the human microbiome are causative of disease initiation and progression. Aykut et al. present data supporting...
A growing body of literature suggests that alterations in the human microbiome are causative of disease initiation and progression. Aykut et al. present data supporting the argument that alterations in the gut fungal microbiome (the “mycobiome”), along with the presence of fungal elements within pancreatic tissue (specifically those of the genus , are associated with pancreatic oncogenesis. Upon analyzing the human sequencing data presented in the original manuscript, we found few fungal reads in pancreatic tissue samples and did not identify differences in pancreatic or gut mycobiome composition between healthy and pancreatic ductal adenocarcinoma (PDAC) patients. Our re-analysis of these data does not support an association between an intrinsic pancreatic mycobiome and the development of human PDAC, and illustrates the challenges in analyzing microbiome sequencing data from low biomass samples.
Topics: Humans; Mycobiome; Pancreatic Neoplasms; Pancreas; Carcinogenesis
PubMed: 37532819
DOI: 10.1038/s41586-023-06292-1 -
ELife Oct 2023The splicing factor SF3B1 is recurrently mutated in various tumors, including pancreatic ductal adenocarcinoma (PDAC). The impact of the hotspot mutation SF3B1 on the...
The splicing factor SF3B1 is recurrently mutated in various tumors, including pancreatic ductal adenocarcinoma (PDAC). The impact of the hotspot mutation SF3B1 on the PDAC pathogenesis, however, remains elusive. Here, we demonstrate that Sf3b1 alone is insufficient to induce malignant transformation of the murine pancreas, but that it increases aggressiveness of PDAC if it co-occurs with mutated KRAS and p53. We further show that Sf3b1 already plays a role during early stages of pancreatic tumor progression and reduces the expression of TGF-β1-responsive epithelial-mesenchymal transition (EMT) genes. Moreover, we found that SF3B1 confers resistance to TGF-β1-induced cell death in pancreatic organoids and cell lines, partly mediated through aberrant splicing of . Overall, our findings demonstrate that SF3B1 acts as an oncogenic driver in PDAC, and suggest that it promotes the progression of early stage tumors by impeding the cellular response to tumor suppressive effects of TGF-β.
Topics: Animals; Humans; Mice; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Mutation; Pancreatic Ducts; Pancreatic Neoplasms; Phosphoproteins; RNA Splicing Factors; Transcription Factors; Transforming Growth Factor beta1
PubMed: 37823551
DOI: 10.7554/eLife.80683 -
Oncology Research 2024Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies. The Kirsten rat sarcoma virus (KRAS) oncogene is mutated in up to 90% of... (Review)
Review
Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies. The Kirsten rat sarcoma virus (KRAS) oncogene is mutated in up to 90% of all pancreatic ductal adenocarcinomas (PDACs) and constitutes an attractive target for therapy. However, the most common KRAS mutations in PDAC are G12D (44%), G12V (34%) and G12R (20%) that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer. KRAS G12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%-3% of PDAC. Recently, the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development. The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor (GEF) Son of Sevenless 1 that drives KRAS. These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.
Topics: Humans; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Mutation; Molecular Targeted Therapy; Carcinoma, Pancreatic Ductal; Antineoplastic Agents; Animals
PubMed: 38686056
DOI: 10.32604/or.2024.045356