A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma.
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ABSTRACT:
SUBMITTER: Hayashi A
PROVIDER: S-EPMC8809486 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma.
Hayashi Akimasa A Fan Jun J Chen Ruoyao R Ho Yu-Jui YJ Makohon-Moore Alvin P AP Lecomte Nicolas N Zhong Yi Y Hong Jungeui J Huang Jinlong J Sakamoto Hitomi H Attiyeh Marc A MA Kohutek Zachary A ZA Zhang Lance L Boumiza Aida A Kappagantula Rajya R Baez Priscilla P Bai Jessica J Lisi Marta M Chadalavada Kalyani K Melchor Jerry P JP Wong Winston W Nanjangud Gouri J GJ Basturk Olca O O'Reilly Eileen M EM Klimstra David S DS Hruban Ralph H RH Wood Laura D LD Overholtzer Michael M Iacobuzio-Donahue Christine A CA
Nature cancer 20200113 1
Pancreatic cancer expression profiles largely reflect a classical or basal-like phenotype. The extent to which these profiles vary within a patient is unknown. We integrated evolutionary analysis and expression profiling in multiregion-sampled metastatic pancreatic cancers, finding that squamous features are the histologic correlate of an RNA-seq-defined basal-like subtype. In patients with coexisting basal and squamous and classical and glandular morphology, phylogenetic studies revealed that s ...[more]
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Project description:Pancreatic cancer expression profiles largely reflect a classical or basal-like phenotype. The extent to which these profiles vary within a patient is unknown. We integrated evolutionary analysis and expression profiling in multiregion sampled metastatic pancreatic cancers, finding that squamous features are the histologic correlate of an RNA-seq defined basal-like subtype. In patients with coexisting basal/squamous and classical/glandular morphology, phylogenetic studies revealed that squamous morphology represented a subclonal population in an otherwise classical/glandular tumor. Cancers with squamous features were significantly more likely to have clonal mutations in chromatin modifiers, intercellular heterogeneity for MYC amplification, and entosis. These data provide a unifying paradigm for integrating basal-type expression profiles, squamous histology, and somatic mutations in chromatin modifier genes in the context of clonal evolution of pancreatic cancer.
| EGAS00001003974 | EGA
Project description:Immunotherapies targeting aspects of T cell functionality are efficacious in many solid tumors, but pancreatic ductal adenocarcinoma (PDAC) remains refractory to these treatments. Deeper understanding of the PDAC immune ecosystem is needed to identify additional therapeutic targets and predictive biomarkers for therapeutic response and resistance monitoring. To address these needs, we quantitatively evaluated leukocyte contexture in 135 human PDACs at single-cell resolution by profiling density and spatial distribution of myeloid and lymphoid cells within histopathologically defined regions of surgical resections from treatment-naive and presurgically (neoadjuvant)-treated patients and biopsy specimens from metastatic PDAC. Resultant data establish an immune atlas of PDAC heterogeneity, identify leukocyte features correlating with clinical outcomes, and, through an in silico study, provide guidance for use of PDAC tissue microarrays to optimally measure intratumoral immune heterogeneity. Atlas data have direct applicability as a reference for evaluating immune responses to investigational neoadjuvant PDAC therapeutics where pretherapy baseline specimens are not available. SIGNIFICANCE: We provide a phenotypic and spatial immune atlas of human PDAC identifying leukocyte composition at steady state and following standard neoadjuvant therapies. These data have broad utility as a resource that can inform on leukocyte responses to emerging therapies where baseline tissues were not acquired.This article is highlighted in the In This Issue feature, p. 1861.
| S-EPMC8338775 | biostudies-literature
Project description:Over a decade of sequencing-based genomics research has unveiled a diverse somatic mutation landscape across patients with pancreatic ductal adenocarcinoma (PDAC), and the identification of druggable mutations has aligned with the development of novel targeted therapeutics. However, despite these advances, direct translation of years of PDAC genomics research into the clinical care of patients remains a critical and unmet need. Technologies that enabled the initial mapping of the PDAC mutation landscape, namely whole-genome and transcriptome sequencing, remain overly expensive in terms of both time and financial resources. Consequentially, dependence on these technologies to identify the relatively small subset of patients with actionable PDAC alterations has greatly impeded enrollment for clinical trials testing novel targeted therapies. Liquid biopsy tumor profiling using circulating tumor DNA (ctDNA) generates new opportunities by overcoming these challenges while further addressing issues particularly relevant to PDAC, namely, difficulty of obtaining tumor tissue via fine-needle biopsy and the need for faster turnaround time due to rapid disease progression. Meanwhile, ctDNA-based approaches for tracking disease kinetics with respect to surgical and therapeutic interventions offer a means to elevate the current clinical management of PDAC toward higher granularity and accuracy. This review provides a clinically focused summary of ctDNA advances, limitations, and opportunities in PDAC and postulates ctDNA sequencing technology as a catalyst for evolving the clinical decision-making paradigm of this disease.
| S-EPMC9989430 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death due to limited advances in recent years in early diagnosis and personalized therapy capable of overcoming tumor resistance to chemotherapy. In the last decades, significant advances have been achieved in the identification of recurrent genetic and molecular alterations of PDAC including those involving the KRAS, CDKN2A, SMAD4, and TP53 driver genes. Despite these common genetic traits, PDAC are highly heterogeneous tumors at both the inter- and intra-tumoral genomic level, which might contribute to distinct tumor behavior and response to therapy, with variable patient outcomes. Despite this, genetic and genomic data on PDAC has had a limited impact on the clinical management of patients. Integration of genomic data for classification of PDAC into clinically defined entities-i.e., classical vs. squamous subtypes of PDAC-leading to different treatment approaches has the potential for significantly improving patient outcomes. In this review, we summarize current knowledge about the most relevant genomic subtypes of PDAC including the impact of distinct patterns of intra-tumoral genomic heterogeneity on the classification and clinical and therapeutic management of PDAC.
| S-EPMC8430663 | biostudies-literature
Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease harboring significant microenvironment heterogeneity, especially for the macrophages. Tumor-associated macrophages (TAMs) orchestrate PDAC malignancy, but their dynamics during disease progression remains poorly understood. There is a pressing need to identify the molecular mechanism underlying tumor-macrophage interactions and thus design novel therapeutic strategies.MethodsHerein, we developed an insilico computational method incorporating bulk and single-cell transcriptome profiling to characterize macrophage heterogeneity. CellPhoneDB algorithm was applied to infer macrophage-tumor interaction networks, whereas pseudotime trajectory for dissecting cell evolution and dynamics.ResultsWe demonstrated myeloid compartment was an interactive hub of tumor microenvironment (TME) essential for PDAC progression. Dimensionality reduction classified seven clusters within the myeloid cells wherein five subsets of macrophages were characterized by diverse cell states and functionality. Remarkably, tissue-resident macrophages and inflammatory monocyte were identified as potential sources of TAMs. Further, we uncovered several ligand-receptor pairs lining tumor cells and macrophages. Among them, HBEGF-CD44, HBEGF-EGFR, LGALS9-CD44, LGALS9-MET, and GRN-EGFR were correlated with worse overall survival. Notably, as in vitro experiments indicated, TAM-derived HBEGF promoted proliferation and invasion of the pancreatic cancer cell line.ConclusionTogether, our work deciphered a comprehensive single-cell atlas of the macrophage compartment of PDAC and provided novel macrophage-tumor interaction features with potential value in developing targeted immunotherapies and molecular diagnostics for predicting patient outcome.
| S-EPMC9983236 | biostudies-literature
Project description:BackgroundThe peritumoral stroma is a hallmark of pancreatic ductal adenocarcinoma (PDA) with implications for disease development, progression and therapy resistance. We systematically investigated immune features of the stroma in PDA patients to identify markers of clinical importance and potential therapeutic targets.MethodsTissue and blood samples of 51 PDA patients with clinical and follow-up information were included. Laser Capture Microdissection allowed us to analyze the stromal compartment in particular. Systematic immunohistochemistry, followed by software-based image analysis were conducted. Also, multiplex cytokine analyses (including 50 immune-related molecules) were performed. Functional analyses were performed using patient-derived 3D bioprints. Clinical information was used for survival analyses. Intercompartmental IL9 and IL18 gradients were assessed in matched samples of tumor epithelium, stroma, and serum of patients. Serum levels were compared to an age-matched healthy control group.ResultsStromal IL9 and IL18 are significantly associated with patient survival. While IL9 is a prognostic favorable marker (p=0.041), IL18 associates with poor patient outcomes (p=0.030). IL9 correlates with an anti-tumoral cytokine network which connects regulation of T helper (Th) 9, Th1 and Th17 cells (all: p<0.05 and r>0.5). IL18 correlates with a Th1-type cytokine phenotype and stromal CXCL12 expression (all: p<0.05 and r>0.5). Further, IL18 associates with a higher level of exhausted T cells. Inhibition of IL18 results in diminished Th1- and Th2-type cytokines. Patients with high stromal IL9 expression have a tumor-to-stroma IL9 gradient directed towards the stroma (p=0.019). Low IL18 expression associates with a tumor-to-stroma IL18 gradient away from the stroma (p=0.007). PDA patients showed higher serum levels of IL9 than healthy controls while serum IL18 levels were significantly lower than in healthy individuals. The stromal immune cell composition is distinct from the tumor epithelium. Stromal density of FoxP3+ regulatory T cells showed a tendency towards improved patient survival (p=0.071).ConclusionAn unexpected high expression of the cytokines IL9 and IL18 at different ends is of significance in the stroma of PDA and relates to opposing patient outcomes. Sub-compartmental cytokine analyses highlight the importance of a differentiated gradient assessment. The findings suggest stromal IL9 and/or IL18 as markers for patient stratification and as potential therapeutic targets. Future steps include investigating e. g. the role of local microbiota as both cytokines are also regulated by microbial compositions.
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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is highly associated with cachexia and weight loss, which is driven by the tumour's effect on the body. Data are lacking on differences in these metrics based on PDAC anatomic location. We hypothesize that the primary tumour's anatomic region influences the prevalence and severity of unintentional weight loss.MethodsTreatment naïve patients with PDAC who underwent pancreatectomy at a single institution between 2012 and 2020 were identified retrospectively. Patients with pancreatic head or distal tumours were matched by sex, age, N and T stage. Serologic and anthropometric variables were obtained at the time of diagnosis. Skeletal muscle index (SMI), muscle radiation attenuation (MRA) and adiposity were measured. The primary outcome was presence of significant weight loss [>5% body weight (BW) loss in past 6 months]. Signed rank tests, Cochran Mantel Haenszel tests and Kaplan-Meier survival analysis are presented. RNA-seq of tumours was performed to explore enriched pathways related to cachexia and weight loss.ResultsPancreatic head tumours (n = 24) were associated with higher prevalence (70.8% vs. 41.7%, P = 0.081) and degree of weight loss (7.9% vs. 2.5%, P = 0.014) compared to distal tumours (n = 24). BMI (P = 0.642), SMI (P = 0.738) and MRA (P = 0.478) were similar between groups. Combining BW loss, SMI and MRA into a composite score, patients with pancreatic head cancers met more criteria associated with poor prognosis (P = 0.142). Serum albumin (3.9 vs. 4.4 g/dL, P = 0.002) was lower and bilirubin (4.5 vs. 0.4 mg/dL, P < 0.001) were higher with pancreatic head tumours. Survival differed by tumour location (P = 0.014) with numerically higher median overall survival with distal tumours (11.1 vs. 21.8 months; P = 0.066). Transcriptomic analysis revealed inactivation of appetite stimulation, weight regulation and nutrient digestion/metabolism pathways in pancreatic head tumours.ConclusionsResectable pancreatic head PDAC is associated with higher prevalence of significant weight loss and more poor prognosis features. Pancreaticobiliary obstruction and hypoalbuminemia in patients with head tumours suggests compounding effects of nutrient malabsorption and systemic inflammation on molecular drivers of cachexia, possibly contributing to shorter survival. Therefore, PDAC-associated cachexia is a heterogenous syndrome, which may be influenced by the primary tumour location. Select patients with resectable pancreatic head tumours may benefit from nutritional rehabilitation to improve outcomes.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas and has one of the highest mortality rates of any cancer type with a 5-year survival rate of <5%. Recent studies of PDAC have provided several transcriptomic classifications based on separate analyses of individual patient cohorts. There is a need to provide a unified transcriptomic PDAC classification driven by therapeutically relevant biologic rationale to inform future treatment strategies. Here, we used an integrative meta-analysis of 353 patients from four different studies to derive a PDAC classification based on immunologic parameters. This consensus clustering approach indicated transcriptomic signatures based on immune infiltrate classified as adaptive, innate and immune-exclusion subtypes. This reveals the existence of microenvironmental interpatient heterogeneity within PDAC and could serve to drive novel therapeutic strategies in PDAC including immune modulation approaches to treating this disease.
| S-EPMC6767191 | biostudies-literature
Project description:Pancreatic ductal adenocarcinoma (PDAC) tumor interpatient heterogeneity has been well described with two major prognostic subtypes (classical and basal-like). An important intrapatient heterogeneity has been reported but has not yet been studied extensively due to the lack of standardized, reproducible, and easily accessible high-throughput methods. We built an immunohistochemical (IHC) tool capable of differentiating RNA-defined classical and basal-like tumors by selecting relevant antibodies using a multistep process. The successive stages of (i) an in silico selection from a literature review and a bulk transcriptome analysis of 309 PDACs, (ii) a tumor-specific selection from 30 patient-derived xenografts and single-cell data, followed by (iii) the validation on tissue microarrays in 50 PDAC were conducted. We used our final IHC panel on two independent cohorts of resected PDAC (n = 95, whole-slide, n = 148, tissue microarrays) for external validation. After digitization and registration of pathology slides, we performed a tile-based analysis in tumor areas to identify relevant marker combinations. Sequential marker selection led to the following panel: GATA6, CLDN18, TFF1, MUC16, S100A2, KRT17, PanBasal. Four different phenotypes were identified: one classical, one intermediate (KRT17+), and two basal-like (MUC16+ versus S100A2+) with specific biological properties. The presence of a minor basal contingent drastically reduced overall survival [hazard ratio (HR) = 1.90, p = 0.03], even in classical predominant PDACs. Analysis of preneoplastic lesions suggested that pancreatic carcinogenesis might follow a progressive evolution from classical toward a basal through an early intermediate phenotype. In conclusion, our IHC panel redefined and easily assessed the high degree of intra- and intertumoral heterogeneity of PDAC. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
| S-EPMC11880971 | biostudies-literature
Project description:Human tumors are characterized by extensive intratumoral transcriptional variability within the cancer cell and stromal compartments. This variation drives phenotypic heterogeneity, producing cell states with differential pro- and anti-tumorigenic properties. While bulk RNA sequencing cannot achieve cell-type-specific transcriptional granularity, single-cell sequencing has permitted an unprecedented view of these cell states. Despite this knowledge, we lack an understanding of the mechanistic drivers of this transcriptional and phenotypic heterogeneity. 3' untranslated region alternative polyadenylation (3' UTR-APA) drives gene expression alterations through regulation of 3' UTR length. These 3' UTR alterations modulate mRNA stability, protein expression and protein localization, resulting in cellular phenotypes including differentiation, cell proliferation, and migration. Therefore, we sought to determine whether 3' UTR-APA events could characterize phenotypic heterogeneity of tumor cell states. Here, we analyze the largest single-cell human pancreatic ductal adenocarcinoma (PDAC) dataset and resolve 3' UTR-APA patterns across PDAC cell states. We find that increased proximal 3' UTR-APA is associated with PDAC progression and characterizes a metastatic ductal epithelial subpopulation and an inflammatory fibroblast population. Furthermore, we find significant 3' UTR shortening events in cell-state-specific marker genes associated with increased expression. Therefore, we propose that 3' UTR-APA drives phenotypic heterogeneity in cancer.
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