Risk Factor For Pancreatic Ductal Adenocarcinoma Research Articles

NFAT5 governs cellular plasticity-driven resistance to KRAS-targeted therapy in pancreatic cancer.

Resistance to KRAS therapy in pancreatic ductal adenocarcinoma (PDAC) involves cellular plasticity, particularly the epithelial-to-mesenchymal transition (EMT), which poses challenges for effective targeting. Chronic pancreatitis, a known risk factor for PDAC, elevates TGFβ levels in the tumor microenvironment (TME), promoting resistance to KRAS therapy. Mechanistically, TGFβ induces the formation of a novel protein complex composed of SMAD3, SMAD4, and the nuclear factor NFAT5, triggering EMT and resistance by activating key mediators such as S100A4. Inhibiting NFAT5 attenuates pancreatitis-induced resistance to KRAS inhibition and extends mouse survival. Additionally, TGFβ stimulates PDAC cells to secrete CCL2, recruiting macrophages that contribute to KRAS bypass through paracrine S100A4. Our findings elucidate the role of TGFβ signaling in EMT-associated KRAS therapy resistance and identify NFAT5 as a druggable target. Targeting NFAT5 could disrupt this regulatory network, offering a potential avenue for preventing resistance in PDAC.

Diagnostic and Prognostic Markers for Pancreatitis and Pancreatic Ductal Adenocarcinoma.

Diagnostic markers are desperately needed for the early detection of pancreatic ductal adenocarcinoma (PDA). We describe sets of markers expressed in temporal order in mouse models during pancreatitis, PDA initiation and progression. Cell type specificity and the differential expression of PDA markers were identified by screening single cell (sc) RNAseq from tumor samples of a mouse model for PDA (KIC) at early and late stages of PDA progression compared to that of a normal pancreas. Candidate genes were identified from three sources: (1) an unsupervised screening of the genes preferentially expressed in mouse PDA tumors; (2) signaling pathways that drive PDA, including the Ras pathway, calcium signaling, and known cancer genes, or genes encoding proteins that were identified by differential mass spectrometry (MS) of mouse tumors and conditioned media from human cancer cell lines; and (3) genes whose expression is associated with poor or better prognoses (PAAD, oncolnc.org). The developmental progression of PDA was detected in the temporal order of gene expression in the cancer cells of the KIC mice. The earliest diagnostic markers were expressed in epithelial cancer cells in early-stage, but not late-stage, PDA tumors. Other early markers were expressed in the epithelium of both early- and late-state PDA tumors. Markers that were expressed somewhat later were first elevated in the epithelial cancer cells of the late-stage tumors, then in both epithelial and mesenchymal cells, or only in mesenchymal cells. Stromal markers were differentially expressed in early- and/or late-stage PDA neoplasia in fibroblast and hematopoietic cells (lymphocytes and/or macrophages) or broadly expressed in cancer and many stromal cell types. Pancreatitis is a risk factor for PDA in humans. Mouse models of pancreatitis, including caerulein treatment and the acinar-specific homozygous deletion of differentiation transcription factors (dTFs), were screened for the early expression of all PDA markers identified in the KIC neoplasia. Prognostic markers associated with a more rapid decline were identified and showed differential and cell-type-specific expression in PDA, predominately in late-stage epithelial and/or mesenchymal cancer cells. Select markers were validated by immunohistochemistry in mouse and human samples of a normal pancreas and those with early- and late-stage PDA. In total, we present 2165 individual diagnostic and prognostic markers for disease progression to be tested in humans from pancreatitis to late-stage PDA.

Abstract 1475: Uncovering the functional variants and target genes of the 7q32 pancreatic cancer risk locus

Abstract In western nations, pancreatic ductal adenocarcinoma (PDAC) is set to become second leading cause of cancer mortality over the next decade. Despite advances in treatment, PDAC has a 5-year survival rate of only ~9%, necessitating a better understanding of its etiology. Risk factors for PDAC are both environmental and genetic, with heritability estimated at around 20%. However, highly penetrant coding variants are rare within the population and have been estimated to account for as little as 1% of the phenotypic variance for PDAC. In an effort to identify common PDAC susceptibility alleles, genome-wide association studies (GWAS) have identified 17 loci at which germline variants associate with PDAC risk. Mostly localizing to non-coding loci, many such risk variants are expected to confer risk via allele-specific changes in transcription factor binding, leading to altered target gene expression over a lifetime. The identification of functional variants from GWAS is complicated by the correlation of alleles through linkage disequilibrium (LD). Here, we have leveraged Bayesian fine mapping to identify a credible set of seven single nucleotide polymorphisms (SNPs) in high LD at the 7q32 risk locus. Fine-mapped variants were annotated using epigenomic datasets we previously generated from a range of pancreatic cell lines, organoids and primary patient samples, encompassing histone modification marks (ChIP-seq), open chromatin (ATAC-seq) and chromatin conformation capture (Capture-HiC, HiChIP). Two variants from the credible set (rs6971499 and rs6970779) were found to consistently lie within regions annotated as super-enhancers and marked by open chromatin within our data. Both SNPs exhibit chromatin looping to the promoters of nearby plausible target genes LINC-PINT and miR29a. Electrophoretic mobility shift assays (EMSA) illustrate that rs6971499-T and rs6970779-G exhibit allele-specific protein binding in PANC-1 and MIA PaCa-2 cell lines, while luciferase reporter assays in the same cell lines demonstrate that both alleles drive significant changes in transcriptional activity. Ongoing proteomic experiments aim to identify the transcription factors differentially bound to these alleles, while CRISPR methods are being employed to validate enhancer variants in their native chromatin context. Future experiments may further characterise these transcription factors and their target genes with an eye toward better understanding their roles in PDAC carcinogenesis. Citation Format: Aidan O'Brien, Jason W. Hoskins, Daina R. Eiser, Katelyn E. Connelly, Jun Zhong, Thorkell Andresson, Irene Collins, Pancreatic Cancer Cohort Consortium, Pancreatic Cancer Case-Control Consortium, Stephen J. Chanock, Alison P. Klein, H. Efsun Arda, Laufey T. Amundadottir. Uncovering the functional variants and target genes of the 7q32 pancreatic cancer risk locus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1475.

Obesity and Pancreatic Cancer: Recent Progress in Epidemiology, Mechanisms and Bariatric Surgery.

More than 30% of people in the United States (US) are classified as obese, and over 50% are considered significantly overweight. Importantly, obesity is a risk factor not only for the development of metabolic syndrome but also for many cancers, including pancreatic ductal adenocarcinoma (PDAC). PDAC is the third leading cause of cancer-related death, and 5-year survival of PDAC remains around 9% in the U.S. Obesity is a known risk factor for PDAC. Metabolic control and bariatric surgery, which is an effective treatment for severe obesity and allows massive weight loss, have been shown to reduce the risk of PDAC. It is therefore clear that elucidating the connection between obesity and PDAC is important for the identification of a novel marker and/or intervention point for obesity-related PDAC risk. In this review, we discussed recent progress in obesity-related PDAC in epidemiology, mechanisms, and potential cancer prevention effects of interventions, including bariatric surgery with preclinical and clinical studies.

Candidate diagnostic and prognostic markers for pancreatitis and pancreatic ductal adenocarcinoma

Diagnostic markers are desperately needed for early detection of pancreatic ductal adenocarcinoma (PDA). We describe sets of markers expressed in temporal order in mouse models during pancreatitis, PDA initiation and progression. Cell type specificity of PDA marker expression was analyzed by interrogating quantitative dot plots of single cell (sc) RNAseq for 3021 candidate genes in tumor samples from a mouse model for PDA (KIC) at early and late stages of PDA progression compared to normal pancreas. Protein markers were identified by differential mass spectrometry (MS) of mouse tumors and conditioned media from human cancer cell lines. Additional candidate genes were identified from signaling pathways that drive PDA, including the Ras pathway, calcium signaling, and known cancer genes. Developmental progression of cancer was revealed in seven classes of PDA markers expressed in cancer cells and stroma. The earliest diagnostic markers (47 genes) were specifically expressed in epithelial cancer cells in early, but not late, PDA tumors. Other markers were first elevated in epithelial cancer cells of late stage tumors (288 genes), or in both epithelial and mesenchymal cells (740 genes), or only in mesenchymal cells (216 genes). Stromal markers were differentially expressed in early‐ and/or late‐PDA neoplasia (594 genes). Pancreatitis is a risk factor for PDA in humans. Mouse models of pancreatitis, including caerulein treatment and acinar‐specific homozygous deletion of differentiation transcription factors (dTFs), were screened for early expression of all PDA markers identified in KIC neoplasia. Select diagnostic markers were validated by immunohistochemistry in mouse and human samples of normal pancreas, early‑ and late‐stage PDA. Prognostic markers from TCGA were identified that showed differential and cell type‐specific expression in PDA. Here we present diagnostic and prognostic markers for disease progression from pancreatitis to late‐stage PDA.

ST6Gal1 Contributes to Pancreatic Cancer Initiation by Promoting Pancreatitis‐Induced Acinar to Ductal Metaplasia

Aberrant glycosylation is one of the earliest known hallmarks of cancer. Amongst the predominate changes in tumor cell glycosylation is an increase in α2‐6 sialylation on N‐glycans, a modification elaborated by the ST6Gal1 sialyltransferase. ST6Gal1 activity dramatically alters cellular function via the sialylation of various surface receptors such as EGFR and TNFR1, resulting in altered signal transduction and gene expression. ST6Gal1 expression is upregulated in multiple cancers, including pancreatic ductal adenocarcinoma (PDAC). Recent studies from our group suggest that the upregulation of ST6Gal1 in pancreatic acinar cells may promote PDAC initiation by facilitating acinar to ductal metaplasia (ADM), a process in which acinar cells de‐differentiate into ductal‐like, progenitor cells. In the nonmalignant pancreas, ADM is induced primarily by pancreatitis, a known risk factor for PDAC. Pancreatitis causes acinar cell apoptosis, however some cells undergo ADM and acquire regenerative capabilities essential for tissue healing. Notably, ADM‐like cells are particularly susceptible to oncogenic transformation. In the current study we determined that ST6Gal1 was strikingly upregulated in pancreatic tissues from chronic pancreatitis patients and mice with experimental pancreatitis. Furthermore, ST6Gal1 was selectively expressed in the ADM‐like cells, as identified both morphologically and by staining for ADM‐specific markers. ST6Gal1 activity was associated with a proliferative phenotype. More than 50% of cells with upregulated ST6Gal1 co‐expressed the proliferative marker, Ki67, whereas activated caspase 8 was undetectable in ST6Gal1‐positive cells. To interrogate a functional role for ST6Gal1 in ADM, we developed genetically‐engineered mice with ST6Gal1 expression in the pancreas (“SC” mice). Importantly, acinar cells from SC mice exhibited ADM‐like characteristics, indicated by increased expression of classic stem and ductal genes. RNASeq analyses comparing SC and WT pancreata indicated that SC cells had an enrichment in: stem cell pathways; a pancreatic ductal cell program; and gene networks associated with pancreatic cancer. Additionally, organoids derived from SC pancreata displayed increased expression of stem and ductal genes relative to WT organoids, as well as greater organoid‐forming potential and growth. To evaluate inflammation‐induced ADM, SC and WT mice were injected with cerulein to induce pancreatitis, and the ADM‐like cells were quantified by examining surface ADM markers by flow cytometry. Following induction of pancreatitis, more ADM‐like cells were present in SC versus WT pancreata. Finally, we crossbred SC mice to the “KC” PDAC model, which expresses oncogenic KRas (KrasG12D) in the pancreas. Mice with dual expression of ST6Gal1 and KrasG12D had greatly accelerated PDAC initiation, progression and mortality as compared with KC mice. Together these data suggest that the upregulation of ST6Gal1 during chronic pancreatitis may prime acinar cells for neoplastic transformation by facilitating ADM.

Diet-Induced Obesity Promotes Liver Metastasis of Pancreatic Ductal Adenocarcinoma via CX3CL1/CX3CR1 Axis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers, and the patients are generally diagnosed with distant metastasis. Liver is one of the preferred organs of distant metastasis, and liver metastasis is the leading cause of death in PDAC. Diet-induced obesity (DIO) is a risk factor for PDAC, and it remains unclear whether and how DIO contributes to liver metastasis of PDAC. In our study, we found that DIO significantly promoted PDAC liver metastasis compared with normal diet (ND) in intrasplenic injection mouse model. RNA-seq analysis for liver metastasis nodules showed that the various chemokines and several chemokine receptors were altered between ND and DIO samples. The expression levels of CX3CL1 and CX3CR1 were significantly upregulated in DIO-induced liver metastasis of PDAC compared to ND. Increased CX3CL1 promoted the recruitment of CX3CR1-expressing pancreatic tumor cells. Taken together, our data demonstrated that DIO promoted PDAC liver metastasis via CX3CL1/CX3CR1 axis.

Activated Pancreatic Stellate Cells Promote Acinar Duct Metaplasia by Disrupting Mitochondrial Respiration and Releasing Reactive Oxygen Species

Background: Chronic Pancreatitis (CP) is a long-term risk factor for pancreatic ductal adenocarcinoma (PDAC), and both diseases share a common etiology. The activation of Pancreatic stellate cells (PaSCs) caused by inflammation of the chronic pancreas plays a pivotal role in the pathology of pancreatic fibrosis and the malignant phenotype of PDAC. However, the central role of activated PaSCs in Acinar-to-Ductal Metaplasia (ADM) remains unknown. Objective: In the present study, we investigated the link between pancreatic fibrosis and ADM and the possible underlying mechanism. Methods: A caerulein-treated mouse CP model was established, and Masson trichrome histochemical stain and Transmission Electron Microscope (TEM) were used to observe stromal fibrosis and cell ultrastructure, respectively. The expression of amylase and cytokeratin 19 (CK19), mitochondria respiration, and reactive oxygen species (ROS) were detected in vitro in the co-culture model of primary pancreatic acinar cells and PaSCs. Results: The activation of PaSCs and pancreatic fibrosis were accompanied by ADM in pancreatic parenchyma in caerulein-treated mice, which was verified by the co-cultivation experiment in vitro. Furthermore, we showed that activated PaSCs promote ADM by disrupting mitochondrial respiration and releasing ROS. The expression of inflammation-and ADM-related genes, including S100A8, S100A9, and CK19, was observed to be up-regulated in pancreatic acinar cells in the presence of activated PaSCs. The expression of S100A9 and CK19 proteins was also up-regulated in acinar cells co-cultured with activated PaSCs. Conclusion: The manipulation of mitochondrial respiration and ROS release is a promising preventive and/or therapeutic strategy for PDAC, and S100A9 is expected to be a therapeutic target to block the ADM process induced by the activation of PaSCs.

Advances in the management of pancreatic ductal adenocarcinoma.

KEY POINTS The incidence of pancreatic ductal adenocarcinoma (PDAC) is rising and PDAC is projected to become the third leading cause of cancer death in Canada.[1][1] Although risk factors for PDAC are known, the reason for its rising incidence is not. Overall survival for this disease at 5 years

1190-P: Diabetes Activates Pancreatic Stellate Cells through RAGE Signaling in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive carcinoma with poor prognosis. Its poor prognosis is ascribed to the extensive fibrotic stroma. Pancreatic stellate cells (PSCs) are major contributors to PDAC fibrosis. Type 2 diabetes (T2D) is an established risk factor for PDAC. The common mechanistic link might be the accumulation of advanced glycation end-products (AGEs) and the signaling through receptor for advanced glycation end-products (RAGE), the receptor for AGEs. Nevertheless, the role of RAGE in PSCs activation was not evaluated in PDAC with T2D. First, PSCs were isolated from male obese T2D model, db/db (db) and db/m (C) mice at 12 weeks of age. mRNA expression of the makers for PSCs activation like TGF-β1, αSMA and collagen type1A1 were significantly increased in PSCs isolated from db compared to C (p<0.01, respectively). To evaluate the implication of RAGE, PSCs isolated from C57BL/6 (WT) and RAGE deleted mice (RKO) were stimulated with 12.5-100 μg/ml AGEs. AGEs increased mRNA expression of TGF-β1, αSMA and collagen type1A1 in WT-PSCs with dose dependent manner (p<0.01, respectively) despite no increase in mRNA expressions in RKO-PSCs. Furthermore, PSCs were isolated from high fat diet induced obese WT and RKO for 8 weeks. The mRNA expressions of TGF-β1, αSMA and collagen type1A1 were comparable between two groups. We evaluated surgically resected human PDAC subjects with T2D (PDT2D, 33 cases) and without T2D (PDNT2D, 83cases). αSMA-labeled PSCs significantly surrounded the ducts with dysplasia in PDT2D compared to PDNT2D (p<0.05). The nuclear expression of NF-κB in stromal cells, which was downstream molecules of RAGE, was significantly higher in PDT2D than PDNT2D (p<0.05). Collectively, RAGE signaling was activated in PSCs in T2D, which could be implicated in severe stromal fibrosis in PDAC. Inhibition of RAGE signaling in PSCs may link to a new therapy, in which the stromal fibrosis and cytokine production are reduced in PDAC with T2D. Disclosure C. Uchida: None. H. Mizukami: None. K. Kudo: None. Y. Yamamoto: None. Funding Japan Society for the Promotion of Science (JP17K17579)

Light at Night and Risk of Pancreatic Cancer in the NIH-AARP Diet and Health Study.

Circadian disruption may play a role in carcinogenesis. Recent research suggests that light at night (LAN), a circadian disruptor, may be a risk factor for cancer. Moreover, LAN has been linked to obesity and diabetes, two risk factors for pancreatic ductal adenocarcinoma (PDAC). Here we examine the relationship between LAN and PDAC in an epidemiologic study of 464,371 participants from the NIH-AARP Diet and Health Study. LAN was estimated from satellite imagery at baseline (1996), and incident primary PDAC cases were ascertained from state cancer registries. Cox proportional hazards models were used to estimate HRs and two-sided 95% confidence intervals (CI) for the association between quintiles of LAN and PDAC in the overall population stratified by sex. Over up to 16.2 years of follow-up, a total of 2,502 incident PDAC were identified in the cohort. Higher estimated LAN exposure was associated with an elevated PDAC risk. Compared with those living in areas in the lowest LAN quintile, those in areas in the highest quintile had a 27% increase PDAC risk [HR (95% CI), 1.24 (1.03-1.49)], with similar risk for men [1.21 (0.96-1.53)] and women [1.28 (0.94-1.75)]. In addition, stronger associations were observed in normal and overweight groups compared with the obese group (P interaction = 0.03). Our results support the hypothesis that LAN and circadian disruption may be risk factors for PDAC. SIGNIFICANCE: Our study suggests that higher LAN is a risk factor for pancreatic cancer, contributing to the growing literature that demonstrates the potentially adverse health effects of light pollution.

Relationship among CT-based abdominal adipose tissue areas and pancreatic ductal adenocarcinoma in male

Purpose It is known that obesity can be a risk factor for many types of cancer, including the pancreas. Visceral obesity rather than overall obesity is held more responsible for this relationship. This study aimed to evaluate the relationship of adipose tissue areas and their distribution (subcutaneous and visceral) with pancreatic ductal adenocarcinoma (PDAC) in male patients. Materials and-Method The medical data and abdominopelvic computed tomography (CT) examinations of male patients diagnosed with PDAC who underwent surgery or a biopsy in our hospital between January 2015 and January 2020 were retrospectively evaluated. An age-matched control group was formed from 49 male patients who underwent CT with a preliminary diagnosis of urinary stone without a history of malignancy and weight loss and no malignancy on CT at the time of presentation. Adipose tissue areas (total [TAT], visceral [VAT] and subcutaneous [SAT]) were measured in both groups, their VAT/TAT, VAT/SAT and SAT/TAT ratios were calculated, and the data were compared between the two groups. Results Patients with PDAC had significantly greater TAT, VAT and SAT areas than the control group (p = 0.002, p = 0.01, and p = 0.003, respectively). However, there was no significant differences in the VAT/TAT, VAT/SAT and SAT/TAT ratios between the two groups (p = 0.60, p = 0.60, and p = 0.73, respectively). Conclusion In this study, all adipose tissue areas (VAT, SAT, and TAT) were shown to be increased in male patients with PDAC. Both visceral obesity and overall obesity present as risk factors for PDAC in male patients.

Changes in glucose tolerance after pancreatectomy in patients with pancreatic ductal adenocarcinoma.

668 Background: Diabetes mellitus (DM) is reported to be related to pancreatic ductal adenocarcinoma (PDAC). Long-standing DM is a risk factor for PDAC, meanwhile, quite a few patients with PDAC develop DM as a paraneoplastic disorder and some papers reported that DM affected prognosis for PDAC. In this study, we investigated pre- and post-operative glucose tolerance in patients with pancreatectomy for PDAC or other disease. Methods: This single-center prospective study included 69 patients with pancreatectomy (40 pancreaticoduodenectomy (PD) and 29 distal pancreatectomy (DP) ) who received 75-g oral glucose tolerance test (OGTT) and glucagon test pre- and one month postoperatively. Plasma glucose, insulin, and C-peptide (CPR) at 0-, 30-, 60-, and 120-min during OGTT; and 0- and 6-min during glucagon test were obtained. These data and survival outcomes were analyzed. Results: There were 20 (29%) PDAC patients: 12 (30%) in PD group and eight (28%) in DP group. Nine patients with PDAC (45%) and seven patients (18%) without PDAC demonstrated DM type in preoperative OGTT. After pancreatectomy, 11 patients (55%) with PDAC and seven patients (15%) without PDAC experienced improvement in OGTT (P=0.0005). Greater improvement in homeostasis model assessment insulin resistance that were obtained by OGTT and used to measure insulin resistance, was noted after surgery in PDAC patients compared with non-PDAC patients (-1.4 vs -0.5 in PD group, P=0.07; -0.8 vs +0.06 P=0.05 in DP group). Delta CPRs obtained by glucagon test were significantly decreased postoperatively (3.0 to 1.1 ng/mL, P<0.0001 in PD group; 3.3 to 1.8 ng/mL, P<0.0001 in DP group). In survival analysis, fasting plasma glucose >110 mg/dL (HR 3.9, 95%CI 1.5-10, P=0.005) and the average of plasma insulin > 25 µIU/mL during OGTT (HR 0.36, 95%CI 0.14-0.93, P=0.035) were significant prognostic factor for PDAC. Conclusions: Pancreatectomy impaired insulin secretion and improve insulin resistance especially in PDAC patients. About half of PDAC patients demonstrated the improvement of glucose tolerance after surgery. Of note, glucose tolerance differed between PDAC and other disease, and affect the survival outcome for PDAC patients.

New-Onset or Exacerbation of Diabetes Mellitus Is a Clue to the Early Diagnosis of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), which accounts for majority of pancreatic cancers, is one of the most lethal human malignancies. Most patients are diagnosed at an advanced stage after symptom development. Early diagnosis of PDAC in asymptomatic subjects is important to improve prognosis. Diabetes mellitus (DM) is a risk factor for PDAC, and DM, especially new-onset DM, has attracted attentions as a diagnostic clue to PDAC. However, the impact of DM as a diagnostic opportunity on the prognosis of PDAC is unclear. We here retrospectively reviewed 489 PDAC patients and compared the clinical characteristics and prognosis according to the opportunities for PDAC diagnosis. PDAC was diagnosed upon presentation of symptoms, such as pain and jaundice, in 318 cases including 151 DM patients, upon new-onset or exacerbation of long-standing DM in 53 asymptomatic patients, and upon incidental detection by medical check-up or follow-up/work-up of other diseases in 118 asymptomatic patients. Asymptomatic patients including those with DM had smaller tumors, earlier disease stage, and higher resectability rates than symptomatic patients. Asymptomatic patients diagnosed in association with DM had better prognosis (median survival time, 771 days) than those diagnosed due to symptoms (343 days, P < 0.001), and similar to those diagnosed by incidental detection (869 days). The survival advantage was not evident in symptomatic patients with DM-associated signs. In conclusion, patients diagnosed in association with DM at asymptomatic stages had better prognosis than those diagnosed with symptoms. DM-associated signs might provide a clue to the early diagnosis of PDAC among asymptomatic subjects.

PRDM14 is overexpressed in chronic pancreatitis prior to pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer that is typically diagnosed at a later stage with metastases and is difficult to treat. Therefore, investigating the mechanism of PDAC initiation is important to aid early‐stage cancer detection. PRDM14 is a transcription factor that maintains pluripotency in embryonic stem cells and is overexpressed in several cancers. We previously reported that PRDM14 is overexpressed and regulates cancer stem‐like phenotypes in PDAC, and herein, we assess whether PRDM14 expression increases prior to tumorigenesis. Through immunohistochemistry analyses of clinical tissues, we detected PRDM14‐positive cells in precursor pancreatic intraepithelial neoplasia and chronic pancreatitis, which is a risk factor for PDAC, lesions. PRDM14 staining in chronic pancreatitis was as high as that in PDAC and cancer adjacent tissues. We induced pancreatitis in mouse models by cerulein injection, and observed that PRDM14 expression increased in chronic pancreatitis models but not in control or acute pancreatitis mice. Moreover, cerulein treatment increased PRDM14 expression in PK‐1 and AsPC‐1 pancreatic cancer cell lines. Our results suggest that inflammation increases the expression of PRDM14, which regulates cancer stem‐like phenotypes, and this occurs prior to PDAC initiation and progression.

Association between the Risk Factors for Pancreatic Ductal Adenocarcinoma and Those for Malignant Intraductal Papillary Mucinous Neoplasm

Background and Aims: Risk factors for pancreatic ductal adenocarcinoma (PDAC) include diabetes mellitus, chronic pancreatitis, obesity, a family history of pancreatic cancer, and a history of smoking or alcohol consumption. The aim of this study was to evaluate the association between risk factors for PDAC and malignant intraductal papillary mucinous neoplasm (IPMN). Methods: The study included 134 consecutive patients with IPMN who underwent surgical resection at Kindai University Hospital between April 2009 and March 2015. Data on the presence or absence of mural nodules (MNs) and risk factors for PDAC were evaluated. Multivariable logistic regression analysis was performed with malignant IPMN as the outcome variable and MNs and risk factors for PDAC as explanatory variables. Results: The odds ratio of malignant IPMN to MNs was 3.88 (95% confidence interval [CI] 1.53-9.84; p = 0.004), whereas that of malignant IPMN to smoking history was 1.66 (95% CI 0.74-3.71; p = 0.22). When the presence of MNs was considered as a predictive factor for malignancy, the sensitivity and specificity were 88.5 and 32.1%, respectively, whereas when the presence of both smoking history and MNs was considered, the specificity improved to 73.2%, with a decrease in sensitivity to 42.3%. Conclusions: The presence of both a smoking history and MNs was a valuable predictive factor for malignant IPMN with high specificity. A smoking history should be considered before surgical resection in addition to the presence of MNs.

Abstract 891: FGF21 prevents high fat diet-induced pancreatic cancer in mice expressing oncogenic Kras

Abstract The genetic landscape of pancreatic cancer shows nearly ubiquitous mutations of Kras. However, expression of mutant Kras alone is not sufficient to drive pancreatic ductal adenocarcinoma (PDAC) in adult mice. Obesity is a metabolic disorder and is a risk factor for PDAC. One of the main factors that contributes to the development of obesity is high-fat consumption. Recent studies have demonstrated that High-Fat-Diet (HFD) can promote oncogenic Kras mediated development of pancreatic intraepithelial neoplasia and PDAC. However, it is not clear why mice with oncogenic KrasG12D expression are predisposed to HFD mediated pancreatic carcinogenesis. Here, we report that Ras activity dramatically reduces the expression of fibroblast growth factor 21 (FGF21). FGF21 is a key mediator of fatty acid oxidation and lipid metabolism. Pharmacological doses of FGF21 lower serum free fatty acids and lead to weight loss in obese mice. FGF21 is highly expressed in pancreatic acinar cells and is a potential autocrine factor. High levels expression of FGFR1 and β-Klotho, key components for specific sites of FGF21 action, were observed on normal control mouse pancreatic acinar cells using both qRT-PCR and immunohistochemistry technics. FGF21 levels were dramatically reduced (∼6-fold) by Cre-mediated knock-in of oncogenic KrasG12D within one week and further decreased by more than 100-fold within 7 months. This effect of KrasG12D may have been mediated by decreased expression of pancreatic transcription factor Mist1, which was also observed. To dissect obesity and oncogenic KrasG12D mediated PDAC, we fed adult KrasG12D expressing mice with HFD or HFD+FGF21. We observed that KrasG12D expressing mice fed with HFD+FGF21 for 9 weeks significantly lower body weight and pancreatic triglyceride, as well as dramatically fewer PanIN lesions and tumor, compared with KrasG12D mice on a HFD without FGF21. FGF21 treatment extended survival of KrasG12D expressing mice on a HFD. Our results suggest that pancreas-derived FGF21 is an important metabolic regulator which is silenced by oncogenic KrasG12D expression and plays an important role in preventing HFD induced PDAC in KrasG12D expressing mice. Citation Format: Weiqin Lu, Yaying Yang, Xiaojie Wang, Yan Liu, Yongde Luo, Robert A. Wolff, James L. Abbruzzese, Craig D. Logsdon. FGF21 prevents high fat diet-induced pancreatic cancer in mice expressing oncogenic Kras. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 891. doi:10.1158/1538-7445.AM2015-891

Aspirin, statins and pancreatic cancer: Is there room for a chemopreventive effect?

Introduction: Pancreatic ductal adenocarcinoma (PDAC) has increasing incidence and poor prognosis. Prevention can be a cornerstone in the fight against this deathly cancer. In this context, chemopreventive action of aspirin and statins might prove interesting. However, published data are conflicting, with effect sometimes limited to subgroups, and the possible combined effect of the two drugs has never been explored. Aims: To investigate the possible protective role of aspirin and statin use and their combination on PDAC occurrence. Patients & methods: Case-control study; risk factors were screened through questionnaires about environmental factors, family and medical history. Cases were matched to controls for age and gender. Results: 338 PDAC patients and 663 matched controls (54% males, mean age 68 in both groups) were enrolled. Aspirin (18.6% vs 21.9%) and statin (18.9% vs 23.1%) use was similar in both groups. Neither >5-year aspirin (6.9% vs 7.9%) or statins use (4.5% vs 7%), nor their combination (9.7% vs 9.5%) were different among cases and controls. Aspirin and statin use showed no association with PDAC also in subgroup analyses for men and smokers. In logistic regression multivariate analysis heavy smoking (OR:2.88, CI95%:1.98-4.19), heavy drinking (OR:2.47, CI95%:1.47-4.16), previous diabetes (OR:1.78, CI95%:1.00-3.14), chronic pancreatitis (OR:19.7, CI95%:2.09-185.32), obesity (OR:1.67, CI95%:1.05-2.65) and PDAC family history (OR:2.6, CI95%:1.28-5.31) were all significant risk factors. Conclusion: A chemopreventive effect for aspirin and statin use, or their combination was not observed in our study, nor for prolonged use or subgroup analysis. In our cohort, drugs use was mostly daily-dose for cardiovascular event prevention and higher doses might be needed. Known risk factors for PDAC were confirmed.

Abstract SY04-04: Vitamin D receptor stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy

Abstract The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) is thought to drive the severe stromal reaction that characterizes PDA. Here we reveal that the vitamin D receptor (VDR) is expressed in activated human pancreatic tumor stroma as well as in in vivo models of pancreatitis, a known risk factor for PDA. Notably, treatment with the VDR ligand calcipotriol markedly reduced inflammation and fibrosis during pancreatitis and a more pronounced form of the disease developed in VDR knockout mice. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state such that ligand-induced stromal remodeling increased intratumoral gemcitabine levels 5-fold and reduced tumor volume. This work describes a molecular strategy through which epigenomic reprogramming of pancreatic tumor stroma rescues/fosters a robust chemotherapeutic response and advocates a reevaluation of vitamin D therapy for PDA. Citation Format: Ronald M. Evans. Vitamin D receptor stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY04-04. doi:10.1158/1538-7445.AM2014-SY04-04

Association of Diabetes Mellitus and Pancreatic Adenocarcinoma: A Meta-Analysis of 88 Studies

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at an advanced, incurable stage. Previous epidemiological data suggests that diabetes mellitus (DM) is a risk factor for PDAC, which may be important in early detection. However, the strength of this association needs to be determined, taking into account a number of recently published studies. A systematic review of the association between DM and PDAC was undertaken by searching electronic databases and journal references from 1973 to 2013. Summary estimates were obtained separately for case-control and cohort studies by means of a 'random effects' approach. Data pertaining to the DM was recorded and plotted at both an individual and study level, with the relative risks (RR) pooled separately to determine the relationship of DM duration and PDAC. A total of 88 independent studies, including 50 cohort and 39 case-control studies were examined. The overall summary-combined RR was 1.97 (95 % CI 1.78-2.18) with marked heterogeneity that could not be clearly attributed to any subgroup analyses. The risk of PDAC was greatest early after the diagnosis of DM but remained elevated long after the diagnosis. The individual-level RR ranged from 6.69 at less than 1 year to 1.36 at 10 years. The results demonstrate a strong association between PDAC and recently diagnosed DM, which may be attributed to a paraneoplastic effect. However, the presence of diabetes also remains a modest risk factor for the development of PDAC long-term. Selective screening of patients with new-onset DM for PDAC needs to be considered.