Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with little improvement in outcomes in recent decades, although the molecular and phenotypic characterization of PDAC ...has contributed to advances in tailored therapies. PDAC is characterized by dense stroma surrounding tumor cells, which limits the efficacy of treatment due to the creation of a physical barrier and immunosuppressive environment. Emerging evidence regarding the microbiome in PDAC implies its potential role in the initiation and progression of PDAC. However, the underlying mechanisms of how the microbiome affects the local tumor microenvironment (TME) as well as the systemic immune system have not been elucidated in PDAC. In addition, therapeutic strategies based on the microbiome have not been established. In this review, we summarize the current evidence regarding the role of the microbiome in the development of PDAC and discuss a possible role for the microbiome in the early detection of PDAC in relation to premalignant pancreatic diseases, such as chronic pancreatitis and intraductal papillary mucinous neoplasm (IPMN). In addition, we discuss the potential role of the microbiome in the treatment of PDAC, especially in immunotherapy, although the biomarkers used to predict the efficacy of immunotherapy in PDAC are still unknown. A comprehensive understanding of tumor-associated immune responses, including those involving the microbiome, holds promise for new treatments in PDAC.
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal human malignancies, owing in part to its propensity for metastasis. Here, we used an organoid culture system to investigate how ...transcription and the enhancer landscape become altered during discrete stages of disease progression in a PDA mouse model. This approach revealed that the metastatic transition is accompanied by massive and recurrent alterations in enhancer activity. We implicate the pioneer factor FOXA1 as a driver of enhancer activation in this system, a mechanism that renders PDA cells more invasive and less anchorage-dependent for growth in vitro, as well as more metastatic in vivo. In this context, FOXA1-dependent enhancer reprogramming activates a transcriptional program of embryonic foregut endoderm. Collectively, our study implicates enhancer reprogramming, FOXA1 upregulation, and a retrograde developmental transition in PDA metastasis.
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•Recurrent changes in enhancer activity are associated with PDA metastasis•FOXA1 drives enhancer reprograming during PDA progression•Manipulation of FOXA1 in PDA cells alters enhancer activity and disease aggressiveness•FOXA1 drives an aberrant developmental transition in PDA toward embryonic endoderm
Large-scale enhancer reprogramming directed by transcription factors such as FOXA1 drives metastasis in the organoid model of pancreatic cancer.
The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative ...transdifferentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (ΔNp63) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. We also demonstrate that TP63-driven enhancer reprogramming promotes aggressive tumor phenotypes, including enhanced cell motility and invasion, and an accelerated growth of primary PDA tumors and metastases in vivo. This process ultimately leads to a powerful addiction of squamous PDA cells to continuous TP63 expression. Our study demonstrates the functional significance of squamous transdifferentiation in PDA and reveals TP63-based reprogramming as an experimental tool for investigating mechanisms and vulnerabilities linked to this aberrant cell fate transition.
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•TP63 reprograms enhancers to drive squamous transdifferentiation in PDA•TP63 expression promotes migration, invasion, and in vivo tumor growth•Sustained TP63 expression is essential for the growth of squamous PDA cells•TP63 regulates an oncogenic network that operates in the squamous subtype of PDA
Somerville et al. report that the transcription factor TP63 is a master regulator of squamous-subtype pancreatic cancer as it reprograms the enhancer landscape to drive squamous transdifferentiation, promoting invasion, migration, in vivo tumor growth, and poor prognosis.
Pancreatic cancer is the most common lethal malignancy, with little improvement in patient outcomes over the decades. The development of early detection methods and effective therapeutic strategies ...are needed to improve the prognosis of patients with this disease. Recent advances in cancer genomics have revealed the genetic landscape of pancreatic cancer, and clinical trials are currently being conducted to match the treatment to underlying mutations. Liquid biopsy-based diagnosis is a promising method to start personalized treatment. In addition to genome-based medicine, personalized models have been studied as a tool to test candidate drugs to select the most efficacious treatment. The innovative three-dimensional organoid culture platform, as well as patient-derived xenografts can be used to conduct genomic and functional studies to enable personalized treatment approaches. Combining genome-based medicine with drug screening based on personalized models may fulfill the promise of precision medicine for pancreatic cancer.
A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. Here, we investigated whether squamous ...trans-differentiation of human and mouse pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous pancreatic cancer cells secrete factors that recruit neutrophils and convert pancreatic stellate cells into cancer-associated fibroblasts (CAFs) that express inflammatory cytokines at high levels. We use gain- and loss-of-function approaches to show that squamous-subtype pancreatic tumor models become enriched with neutrophils and inflammatory CAFs in a p63-dependent manner. These effects occur, at least in part, through p63-mediated activation of enhancers at pro-inflammatory cytokine loci, which includes
and
as key targets. Taken together, our findings reveal enhanced tissue inflammation as a consequence of squamous trans-differentiation in pancreatic cancer, thus highlighting an instructive role of tumor cell lineage in reprogramming the stromal microenvironment.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stromal reaction (desmoplasia). We have previously reported that mice with conditional Kras
mutation and knockout of TGF-β receptor ...type II (Tgfbr2), PKF mice, develop PDAC with desmoplasia modulated by CXC chemokines that are produced by PDAC cells through tumor-stromal interaction. In this study, we further discovered that PDAC and cancer-associated fibroblast (CAF) accelerated each other's invasion and migration through the CXC chemokines-receptor (CXCLs-CXCR2) axis. Heterozygous knockout of Cxcr2 in PKF mice (PKF2h mice) prolonged survival and inhibited both tumor angiogenesis and PDAC microinvasion. Infiltration of neutrophils, myeloid-derived suppressor cells (MDSCs), and arginase-1
M2-like tumor-associated macrophages (TAMs) significantly decreased in the tumors of PKF2h mice, whereas inducible nitric oxide synthase (iNOS)
M1-like TAMs and apoptotic tumor cells markedly increased, which indicated that blockade of the CXCLs-CXCR2 axis resulted in a shift of immune-inflammatory microenvironment. These results suggest that blocking of the CXCLs-CXCR2 axis in tumor-stromal interactions could be a therapeutic approach against PDAC progression.
Objective It has been discussed whether IgG4-related disease (IgG4-RD), including autoimmune pancreatitis (AIP), is associated with malignancy; however, the issue has not been clarified. Methods We ...analyzed 113 patients with IgG4-RD in whom malignancy was not diagnosed at the time of IgG4-RD onset and the follow-up period was longer than six months. A total of 95 patients had AIP. The mean follow-up period was 73 months. The incidence of the observed malignancies was compared with the expected incidence in an age- and sex-matched general Japanese population based on the Vital Statistics of Japan. Results There were 15 malignancies (lung cancer in five patients, pancreatic cancer in two patients, gastric cancer in two patients, bile duct cancer in one patient, renal cancer in one patient, breast cancer in one patient, tongue cancer in one patient, malignant melanoma in one patient and acute myeloid leukemia in one patient) in 14 patients during the follow-up period. The calculated standardized incidence rate of the total malignancies was not significant, that is, 1.04 (95% CI 0.57-1.75). Conclusion The incidence of total malignancies in IgG4-RD patients is similar to that observed in the general population. At present, it is reasonable to conclude that IgG4-RD is not associated with an increased incidence of total malignancies.
Pancreatic cancer is one of the malignant diseases with the worst prognosis. Resistance to chemotherapy is a major difficulty in treating the disease. We analyzed plasma samples from a genetically ...engineered mouse model of pancreatic cancer and found soluble vascular cell adhesion molecule-1 (sVCAM-1) increases in response to gemcitabine treatment. VCAM-1 was expressed and secreted by murine and human pancreatic cancer cells. Subcutaneous allograft tumors with overexpression or knock-down of VCAM-1, as well as VCAM-1-blocking treatment in the spontaneous mouse model of pancreatic cancer, revealed that sVCAM-1 promotes tumor growth and resistance to gemcitabine treatment in vivo but not in vitro. By analyzing allograft tumors and co-culture experiments, we found macrophages were attracted by sVCAM-1 to the tumor microenvironment and facilitated resistance to gemcitabine in tumor cells. In a clinical setting, we found that the change of sVCAM-1 in the plasma of patients with advanced pancreatic cancer was an independent prognostic factor for gemcitabine treatment. Collectively, gemcitabine treatment increases the release of sVCAM-1 from pancreatic cancer cells, which attracts macrophages into the tumor, thereby promoting the resistance to gemcitabine treatment. sVCAM-1 may be a potent clinical biomarker and a potential target for the therapy in pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different ...prognoses have been elaborated; however, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts. Our model enables distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively. Parameters that influence PDAC subtype specification in this intraductal model include cell plasticity and hyperactivation of the RAS pathway. Finally, through intratumoral dissection and the direct manipulation of
gene dosage, we identify a suite of
-regulated secreted and membrane-bound proteins that may represent potential candidates for therapeutic intervention in patients with PDAC. SIGNIFICANCE: Accurate modeling of the molecular subtypes of pancreatic cancer is crucial to facilitate the generation of effective therapies. We report the development of an intraductal organoid transplantation model of pancreatic cancer that models the progressive switching of subtypes, and identify stochastic and RAS-driven mechanisms that determine subtype specification.
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Background
Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of pancreatic masses is an established procedure for obtaining a pathological specimen. However, application of suction during ...EUS-FNA is still controversial and the efficacy of the slow-pull technique was recently reported for new core biopsy needles.
Aim
The purpose of this study was to compare the suction and slow-pull techniques using regular FNA needles.
Methods
The diagnostic yield of the suction and slow-pull techniques was retrospectively studied for patients who underwent EUS-FNA for pancreatic solid lesions.
Results
A total of 367 passes (181 by suction and 186 by the slow-pull technique) were performed during 97 EUS-FNA procedures for 93 patients with pancreatic solid lesions. The slow-pull technique resulted in lower scores for cellularity (≥2 for 37.5 % vs. 76.7 %) but scores for contamination with blood were lower (≥2 for 25.0 % vs. 66.7 %) and sensitivity of diagnosis of malignancy was higher (90.0 % vs. 67.9 %) when a 25-gauge FNA needle was used. There were no significant differences between the two techniques when a 22-gauge needle was used. In multivariate analysis of 82 cases with malignancy, the slow-pull technique (odds ratio (OR) 1.92,
P
= 0.028), tumor size ≥25 mm (OR 4.64,
P
< 0.001), and tumor location in the body or tail (OR 2.82,
P
< 0.001) were associated with greater sensitivity.
Conclusion
The slow-pull technique was associated with less contamination with blood and can potentially increase the diagnostic yield compared with the suction technique in EUS-FNA of pancreatic solid masses, especially with a 25-gauge FNA needle.
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