Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy that often presents clinically at an advanced stage and that may be confused with chronic pancreatitis (CP). Conversely, CP may be misdiagnosed as PDAC leading to unwarranted pancreas resection. Therefore, early PDAC diagnosis and clear differentiation between PDAC and CP are crucial for improved care. Exosomes are circulating micro-vesicles whose components can serve as cancer biomarkers. We compared exosomal glypican-1 (GPC1) and microRNA levels in normal control subjects and in patients with PDAC and CP. We report that exosomal GPC1 is not diagnostic for PDAC, whereas high exosomal levels of microRNA-10b, (miR-10b), miR-21, miR-30c, and miR-181a and low miR-let7a readily differentiate PDAC from normal control and CP samples. By contrast with GPC1, elevated exosomal miR levels decreased to normal values within 24 h following PDAC resection. All 29 PDAC cases exhibited significantly elevated exosomal miR-10b and miR-30c levels, whereas 8 cases had normal or slightly increased CA 19-9 levels. Thus, our exosomal miR signature is superior to exosomal GPC1 or plasma CA 19-9 levels in establishing a diagnosis of PDAC and differentiating between PDAC and CP.

OBJECTIVES:Accurate peripheral markers for the diagnosis of pancreatic ductal adenocarcinoma (PDAC) are lacking. We measured the differential expression of select microRNAs (miRNAs) in plasma and bile among patients with PDAC, chronic pancreatitis (CP), and controls.METHODS:We identified patients (n=215) with treatment-naive PDAC (n=77), CP with bile/pancreatic duct pathology (n=67), and controls (n=71) who had been prospectively enrolled in a Pancreatobiliary Biorepository at the time of endoscopic retrograde cholangiopancreatography or endoscopic ultrasound. Controls were patients with choledocholithiasis but normal pancreata. The sample was separated into training (n=95) and validation (n=120) cohorts to establish and then test the performance of PDAC Signature Panels in diagnosing PDAC. The training cohort (n=95) included age-matched patients with PDAC, CP, and controls. Panels were derived from the differential expression of 10 candidate miRNAs in plasma or bile. We selected miRNAs having excellent accuracy for inclusion in regression models.RESULTS:Using the training cohort, we confirmed the differential expression of 9/10 miRNAs in plasma (miR-10b, -30c, -106b, -132, -155, -181a, -181b, -196a, and -212) and 7/10 in bile (excluding miR-21, -132, and -181b). Of these, five (miR-10b, -155, -106b, -30c, and -212) had excellent accuracy for distinguishing PDAC. In the training and validation cohorts, the sensitivity/specificity for a PDAC Panel derived from plasma was 95/100% and 100/100%, respectively; in bile, these were 96/100% and 100/100%.CONCLUSIONS:Increased expression of miRNA-10b, -155, and -106b in plasma appears highly accurate in diagnosing PDAC. Additional studies are needed to confirm this Panel and explore its value as a prognostic test.

Trisomy 21 (Ts21) affects craniofacial precursors in individuals with Down syndrome (DS). The resultant craniofacial features in all individuals with Ts21 may significantly affect breathing, eating and speaking. Using mouse models of DS, we have traced the origin of DS-associated craniofacial abnormalities to deficiencies in neural crest cell (NCC) craniofacial precursors early in development. Hypothetically, three copies of Dyrk1a (dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A), a trisomic gene found in most humans with DS and mouse models of DS, may significantly affect craniofacial structure. We hypothesized that we could improve DS-related craniofacial abnormalities in mouse models using a Dyrk1a inhibitor or by normalizing Dyrk1a gene dosage. In vitro and in vivo treatment with Epigallocatechin-3-gallate (EGCG), a Dyrk1a inhibitor, modulated trisomic NCC deficiencies at embryonic time points. Furthermore, prenatal EGCG treatment normalized some craniofacial phenotypes, including cranial vault in adult Ts65Dn mice. Normalization of Dyrk1a copy number in an otherwise trisomic Ts65Dn mice normalized many dimensions of the cranial vault, but did not correct all craniofacial anatomy. These data underscore the complexity of the gene–phenotype relationship in trisomy and suggest that changes in Dyrk1a expression play an important role in morphogenesis and growth of the cranial vault. These results suggest that a temporally specific prenatal therapy may be an effective way to ameliorate some craniofacial anatomical changes associated with DS.

Non-invasive biomarkers for early pancreatic ductal adenocarcinoma (PDAC) diagnosis and disease risk stratification are greatly needed. We conducted a nested case-control study within the Prospective Investigation into Cancer and Nutrition (EPIC) cohort to evaluate pre-diagnostic microRNAs (miRs) as biomarkers of subsequent PDAC risk. A panel of eight miRs (miR-10a, -10b, -21-3p, -21-5p, -30c, -106b, -155, and -212) based on previous evidence from our group was evaluated in 225 microscopically confirmed PDAC cases and 225 controls matched on center, sex, fasting status, and age/date/time of blood collection. MiR levels in pre-diagnostic plasma samples were determined by quantitative RT-PCR. Logistic regression was used to model levels and PDAC risk, adjusting for covariates, and to estimate area under the receiver operating characteristic curves (AUC). Plasma miR-10b, -21-5p, -30c and -106b levels were significantly higher in cases diagnosed within 2 yr of blood collection compared to matched controls (all P-values <0.04). Based on adjusted logistic regression models, levels for six miRs (miR-10a, -10b, -21-5p, -30c, -155, and -212) overall, and for four miRs (-10a, -10b, -21-5p, and -30c) at shorter follow-up time between blood collection and diagnosis (≤5 yr, ≤2 yr), were statistically significantly associated with risk. A score based on the panel showed a linear dose-response trend with risk (P-value=0.0006). For shorter follow-up (≤5 yr), AUC for the score was 0.73, and for individual miRs ranged from 0.73 (miR-212) to 0.79 (miR-21-p).

Total pancreatectomy with islet autotransplantation (TPIAT) is being used increasingly as a definitive treatment for chronic pancreatitis. Patients with chronic pancreatitis have an elevated risk of pancreatic cancer, which can also masquerade as acute or chronic pancreatitis, making the diagnosis challenging. We describe here the first case of pancreatic ductal adenocarcinoma developing in the liver of a patient after TPIAT for presumed benign chronic pancreatitis. Retrospective analysis of the patient’s preoperative serum revealed normal carbohydrate antigen 19-9 and carcinoembryonic antigen levels but elevated levels of microRNAs -10b, -30c, and -106b compared with controls. Screening guidelines are important to reduce the risk of transplantation of malignant tissue. More sensitive screening tools, including the potential use of microRNAs, are needed to detect early preclinical disease, given the highly malignant nature of pancreatic cancer.

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Pancreatic ductal adenocarcinoma (PDAC) is a treatment-recalcitrant malignancy that harbors several key driver mutations at a high frequency (e.g., KRAS, TP53, CDKN2A, and SMAD4&lt;), as well numerous driver mutations that occur at a relatively low and variable frequency among patients with PDAC. Heparan-sulfate proteoglycans (HSPGs) constitute a large family of glycanated proteins that modulate numerous cellular processes and interact with components of the extracellular matrix (ECM) and with heparin-binding growth factors such as heparin binding EGF-like growth factor (HBEGF) that activates the EGF receptor (EGFR) and transforming growth factor beta (TGF-beta) moieties. Syndecan-4 (SDC4) is a transmembrane HSPG that has critical roles in focal adhesion formation, cytoskeletal attachment, cell contractility and motility, and cell signaling, especially in relation to pathways activated by heparin-binding growth factors. To date, the role of SDC4 in PDAC has not been clearly elucidated. Yet, data from 1,034 PDAC samples in The Cancer Genome Atlas (TCGA) revealed that 19% of these samples exhibited altered SDC4 expression, a majority of which were either gain-of-function or amplification alterations often co-occurring with enhanced TGF-beta1 expression, thus underscoring the potential importance of SDC4 in PDAC. Given that TGF-beta1 increases SDC4 expression whereas SDC4 modulates TGF-beta1 actions and interacts with EGFR, we sought to test the hypothesis that SDC4 contributes to PDAC’s progression. Accordingly, we established a novel genetically engineered mouse model (GEMM) of PDAC in which pancreas-specific Cre-mediated expression of oncogenic Kras was combined with deletion of a conditional Ink4a/Arf allele in the presence or absence of SDC4: Pdx1-Cre;LSL-KrasG12D;Ink4a/Arflox/lox;Sdc4-/-, termed KIS4-/-C mice. By comparison with control KIS4 animals, KIS4-/-C mice exhibited attenuated pancreatic tumor growth and markedly prolonged survival. There was attenuation of cancer cell proliferation in the tumors, as determined by Ki67 staining, as well as decreased desmoplasia as evidenced by Mason trichrome staining. By contrast, KIS4+/-C animals with heterozygous loss of SDC4 only exhibited a modest survival advantage by comparison with control KIS4 animals. Taken together, these findings suggest that strategies based on suppressing SDC4 expression and/or function may yield new therapeutic approaches in PDAC. (Supported in part by National Cancer Institute grant CA-075059 to M.K.) Citation Format: Samantha McElyea, Murray Korc. The glycosaminoglycan syndecan-4 facilitates pancreatic cancer progression and biologic aggressiveness [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C31.

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