A neuroligin-2-YAP axis regulates progression of pancreatic intraepithelial neoplasia.

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a dismal prognosis that arises from precursor lesions called pancreatic intraepithelial neoplasias (PanINs). Progression from low- to high-grade PanINs is considered as tumor initiation, and a deeper understanding of this switch is needed. Here, we show that synaptic molecule neuroligin-2 (NLGN2) is expressed by pancreatic exocrine cells and plays a crucial role in the regulation of contact inhibition and epithelial polarity, which characterize the switch from low- to high-grade PanIN. NLGN2 localizes to tight junctions in acinar cells, is diffusely distributed in the cytosol in low-grade PanINs and is lost in high-grade PanINs and in a high percentage of advanced PDACs. Mechanistically, NLGN2 is necessary for the formation of the PALS1/PATJ complex, which in turn induces contact inhibition by reducing YAP function. Our results provide novel insights into NLGN2 functions outside the nervous system and can be used to model PanIN progression.

Dichotomous role of the serine/threonine kinase MAP4K4 in pancreatic ductal adenocarcinoma onset and metastasis through control of AKT and ERK pathways.

MAP4K4 is a serine/threonine kinase of the STE20 family involved in the regulation of actin cytoskeleton dynamics and cell motility. It has been proposed as a target of angiogenesis and inhibitors show potential in cardioprotection. MAP4K4 also mediates cell invasion in vitro, is overexpressed in various types of cancer, and is associated with poor patient prognosis. Recently, MAP4K4 has been shown to be overexpressed in pancreatic cancer, but its role in tumour initiation, progression, and metastasis is unknown. Here, using the KrasG12D Trp53R172H Pdx1-Cre (KPC) mouse model of pancreatic ductal adenocarcinoma (PDAC), we show that deletion of Map4k4 drives tumour initiation and progression. Moreover, we report that the acceleration of tumour onset is also associated with an overactivation of ERK and AKT, two major downstream effectors of KRAS, in vitro and in vivo. In contrast to the accelerated tumour onset caused by loss of MAP4K4, we observed a reduction in metastatic burden with both the KPC model and in an intraperitoneal transplant assay indicating a major role of MAP4K4 in metastatic seeding. In summary, our study sheds light on the dichotomous role of MAP4K4 in the initiation of PDAC onset, progression, and metastatic dissemination. It also identifies MAP4K4 as a possible druggable target against pancreatic cancer spread, but with the caveat that targeting MAP4K4 might accelerate early tumorigenesis. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Pancreatic carcinoma, its variants and precursors: Overview of the current WHO classification.

Pancreatic carcinoma is a relatively common malignant tumor with increasing incidence and mortality. The tumor is usually diagnosed at an advanced stage and generally has a poor prognosis, with only 5% of patients surviving 5 years from the time of diagnosis. The stage of the disease at the time of diagnosis is a crucial factor for the prognosis; 25% of patients with localized tumors survive 3 years from diagnosis, compared to only 1% of those with generalized tumors. Radical surgical removal of the tumor (partial or total pancreatectomy) is a key factor in improving survival. Therefore, the topic is highly relevant to surgeons. Statistics on pancreatic carcinoma mainly focus on ductal adenocarcinoma, which is the most common and least favorable malignant tumor of the pancreas. This review focuses on ductal adenocarcinoma, its variants, and precancerous lesions. The article summarizes information from the latest WHO classification of 2019, which was released 11 years after the previous edition. Compared to the previous version, this new WHO classification introduced rather minor changes in the field of ductal adenocarcinoma. The delineation of rare variants of ductal adenocarcinoma is justified based on genetic and morphological similarities and clinical relevance, as individual subtypes significantly differ in prognosis. The article also includes a description of macroscopic and microscopic precursors of ductal adenocarcinoma and their definitions. Genetic and immunohistochemical differential diagnostic aspects are briefly discussed, as these are more relevant to pathologists than to surgeons.

Acinar-to-Ductal Metaplasia (ADM): On the Road to Pancreatic Intraepithelial Neoplasia (PanIN) and Pancreatic Cancer.

Adult pancreatic acinar cells show high plasticity allowing them to change in their differentiation commitment. Pancreatic acinar-to-ductal metaplasia (ADM) is a cellular process in which the differentiated pancreatic acinar cells transform into duct-like cells. This process can occur as a result of cellular injury or inflammation in the pancreas. While ADM is a reversible process allowing pancreatic acinar regeneration, persistent inflammation or injury can lead to the development of pancreatic intraepithelial neoplasia (PanIN), which is a common precancerous lesion that precedes pancreatic ductal adenocarcinoma (PDAC). Several factors can contribute to the development of ADM and PanIN, including environmental factors such as obesity, chronic inflammation and genetic mutations. ADM is driven by extrinsic and intrinsic signaling. Here, we review the current knowledge on the cellular and molecular biology of ADM. Understanding the cellular and molecular mechanisms underlying ADM is critical for the development of new therapeutic strategies for pancreatitis and PDAC. Identifying the intermediate states and key molecules that regulate ADM initiation, maintenance and progression may help the development of novel preventive strategies for PDAC.

Multimodal 3-D/2-D human islet and duct imaging in exocrine and endocrine lesion environment: associated pancreas tissue remodeling.

Pancreatic intraepithelial neoplasia (PanIN) and islet cell microadenoma are exocrine and endocrine neoplasms of human pancreas that have been linked to pancreatic ductal adenocarcinoma (PDAC) and neuroendocrine tumor, respectively. However, in health and at the surgical margin of pancreatic cancer, it remains unresolved how to simultaneously characterize duct and islet remodeling to investigate the exocrine-endocrine association in the lesion microenvironment. Here, we develop a new vibratome-based approach to detect, confirm, and analyze the two types of pancreas remodeling via stereo/three-dimensional (3-D) and classic/two-dimensional (2-D) histology. Surgical margins of PDAC (n = 10, distal) and cadaveric donor pancreases (n = 10, consecutive cases) were fixed, sectioned by vibratome (350 µm), and surveyed for PanIN and microadenoma via stereomicroscopy. After lesion detection, PanIN and microadenoma were analyzed with 3-D fluorescence imaging and clinical microtome-based histology for confirmation and assessment of microenvironment. Multimodal imaging of PDAC surgical margins and cadaveric donor pancreases detected the peri-PanIN islet aggregation with duct-islet cell clusters. Organ-wide survey of cadaveric donor pancreases shows a marked 2.3-fold increase in the lesion size with the PanIN-islet association vs. without the association. In the survey, we unexpectedly detected the islet cell microadenoma adjacent to (<2 mm) PanIN. Overall, among the 53 early lesions in the cadaveric donor pancreases (PanINs and microadenomas), 81% are featured with the associated exocrine-endocrine tissue remodeling. Multimodal 3-D/2-D tissue imaging reveals local and simultaneous duct and islet remodeling in the cancer surgical margin and cadaveric donor pancreas. In the cadaveric donor pancreas, the peri-PanIN islet aggregation and PanIN-microadenoma association are two major features of pancreas remodeling in the early lesion microenvironment.NEW & NOTEWORTHY We develop a new multimodal 3-D/2-D imaging approach (matched stereomicroscopic, fluorescence, and H&E signals) to examine human duct-islet association in the PDAC surgical margin and cadaveric donor pancreas. In both conditions, peri-PanIN islet aggregation with duct-islet cell clusters was identified. The PanIN-islet cell microadenoma association was unexpectedly detected in the donor pancreas. Our work provides the technical and morphological foundations to simultaneously characterize human islets and ducts to study their association in health and disease.

Pancreatic cancer pathology viewed in the light of evolution.

One way to understand ductal adenocarcinoma of the pancreas (pancreatic cancer) is to view it as unimaginably large numbers of evolving living organisms interacting with their environment. This "evolutionary view" creates both expected and surprising perspectives in all stages of neoplastic progression. Advances in the field will require greater attention to this critical evolutionary prospective.

Endoscopic approach in the diagnosis of high-grade pancreatic intraepithelial neoplasia.

Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is essential for improving prognosis; however, diagnosing PDAC at an early stage is challenging. In patients with localized high-grade pancreatic intraepithelial neoplasia (HG-PanIN), whose tumorous lesion is undetectable on cross-sectional images such as computed tomography or magnetic resonance image, long-term survival is expected. Pancreatic cystic lesions or main pancreatic duct (MPD) dilatation are important indirect findings for the initial diagnosis of HG-PanIN. Magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound (EUS) should play important roles in detecting abnormal image findings, such as local irregular MPD stenosis, caliber MPD changes, small cystic lesions, or branch duct dilatation. Additionally, EUS could detect hypoechoic areas around the MPD stenosis in some patients with HG-PanIN. Subsequently, endoscopic retrograde cholangiopancreatography (ERCP) and its associated pancreatic juice cytology, including serial pancreatic juice aspiration cytologic examination (SPACE) after placement of an endoscopic nasopancreatic drainage (ENPD) tube, may have high diagnostic accuracy for confirming the malignancy in HG-PanIN. Although ERCP and its associated pancreatic cytology, including SPACE, may be associated with post-ERCP pancreatitis (PEP), a recent randomized trial suggested that a 4-Fr ENPD tube may reduce the incidence of PEP. In the future, further prospective multicenter studies are required to establish a standard method of SPACE. Additionally, further studies for novel biomarkers could help to establish evolutionary methods with duodenal fluid and pancreatic juice for the early and accurate diagnosis of early-stage PDAC.

Local islet remodelling associated with duct lesion-islet complex in adult human pancreas.

AIMS/HYPOTHESIS: Islets are thought to be stably present in the adult human pancreas to maintain glucose homeostasis. However, identification of the pancreatic intraepithelial neoplasia (PanIN)-islet complex in mice and the presence of PanIN lesions in adult humans suggest that similar remodelling of islet structure and environment may occur in the human pancreas. To identify islet remodelling in a clinically related setting, we examine human donor pancreases with 3D histology to detect and characterise the human PanIN-islet complex. METHODS: Cadaveric donor pancreases (26-65 years old, n = 10) were fixed and sectioned (350 µm) for tissue labelling, clearing and microscopy to detect local islet remodelling for 3D analysis of the microenvironment. The remodelled microenvironment was subsequently examined via microtome-based histology for clinical assessment. RESULTS: In nine pancreases, we identified the unique peri-lobular islet aggregation associated with the PanIN lesion (16 lesion-islet complexes detected; size: 3.18 ± 1.34 mm). Important features of the lesion-islet microenvironment include: (1) formation of intra-islet ducts, (2) acinar atrophy, (3) adipocyte association, (4) inflammation (CD45+), (5) stromal accumulation (α-SMA+), (6) increase in Ki-67 proliferation index but absence of Ki-67+ alpha/beta cells and (7) in-depth and continuous duct-islet cell contacts, forming a cluster. The duct-islet cell cluster and intra-islet ducts suggest likely islet cell neogenesis but not replication. CONCLUSIONS/INTERPRETATION: We identify local islet remodelling associated with PanIN-islet complex in the adult human pancreas. The tissue remodelling and the evidence of inflammation and stromal accumulation suggest that the PanIN-islet complex is derived from tissue repair after a local injury.

Epithelial cell transforming 2 is regulated by Yes-associated protein 1 and mediates pancreatic cancer progression and metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is highly metastatic and represents one of the deadliest forms of human cancers. Previous studies showed that activation of Yes-associated protein 1 (YAP1) plays a key role in malignant transformation in the pancreas. In this study, we found that YAP1 regulates the expression of epithelial cell transforming 2 (ECT2), a guanine nucleotide exchange factor for Rho-like GTPases. By immunohistochemistry analysis of human tissues, we show that ECT2 is highly expressed in primary PDAC and liver metastasis but not in normal pancreas. These correlations were also observed in a mouse model of PDAC, where pancreatic transformation is driven by mutants of Kras and Trp53. Notably, nuclear ECT2 is upregulated in the transition from preneoplastic lesions to PDAC. High levels of YAP1 or ECT2 expression correlates with the poor overall survival rate of patients with PDAC. We further demonstrate that ECT2 is required for pancreatic cancer cell proliferation and migration in vitro. Finally, using a syngeneic orthotopic xenograft mouse model for pancreatic cancer, we found that ablation of ECT2 expression reduces pancreatic cancer growth and dissemination to the liver. These findings highlight the critical role of ECT2 in promoting pancreatic cancer growth and metastasis and provides insights into the development of novel methods for early detection and treatment.NEW & NOTEWORTHY Pancreatic ductal adenocarcinoma is one of the deadliest forms of human cancers. In this study, we identified a novel signaling mechanism involved in PDAC progression and metastasis. Yes-associated protein 1 mediates the expression of epithelial cell transforming 2, which is elevated in PDAC and correlates with poor survival. Epithelial cell transforming 2 is required for PDAC growth and metastasis. This study provides insights into the development of novel methods for early detection and treatment of PDAC.

Carcinogenesis of Pancreatic Ductal Adenocarcinoma.

Although the estimated time for development of pancreatic ductal adenocarcinoma (PDA) is more than 20 years, PDAs are usually detected at late, metastatic stages. PDAs develop from duct-like cells through a multistep carcinogenesis process, from low-grade dysplastic lesions to carcinoma in situ and eventually to metastatic disease. This process involves gradual acquisition of mutations in oncogenes and tumor suppressor genes, as well as changes in the pancreatic environment from a pro-inflammatory microenvironment that favors the development of early lesions, to a desmoplastic tumor microenvironment that is highly fibrotic and immune suppressive. This review discusses our current understanding of how PDA originates.

Guidelines on management of pancreatic cysts detected in high-risk individuals: An evaluation of the 2017 Fukuoka guidelines and the 2020 International Cancer of the Pancreas Screening (CAPS) consortium statements.

BACKGROUND: Objectives: Pancreatic cysts are frequently detected in high-risk individuals (HRI) undergoing surveillance for pancreatic cancer. The International Cancer of the Pancreas Screening (CAPS) Consortium developed consensus recommendations for surgical resection of pancreatic cysts in HRI that are similar to the Fukuoka guidelines used for the management of sporadic cysts. We compared the performance characteristics of CAPS criteria for pancreatic cyst management in HRI with the Fukuoka guidelines originally designed for the management of cysts in non-HRI. METHODS: Using prospectively collected data from CAPS studies, we determined for each patient with resected screen-detected cyst(s) whether Fukuoka guidelines or CAPS consensus statements would have recommended surgery. We compared sensitivity, specificity, PPV, NPV, and Receiver Operator Characteristics (ROC) curves of these guidelines at predicting the presence of high-grade dysplasia or invasive cancer in pancreatic cysts. RESULTS: 356/732 HRI had ≥ one pancreatic cyst detected; 24 had surgery for concerning cystic lesions. The sensitivity, specificity, PPV, and NPV for the Fukuoka criteria were 40%, 85%, 40%, and 85%, while those of the CAPS criteria were 60%, 85%, 50%, 89%, respectively. ROC curve analyses showed no significant difference between the Fukuoka and CAPS criteria. CONCLUSIONS: In HRI, the CAPS and Fukuoka criteria are moderately specific, but not sufficiently sensitive for detecting advanced neoplasia in cystic lesions. New approaches are needed to guide the surgical management of cystic lesions in HRI.

Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis.

There are increased opportunities in oncology clinics to identify multiple pancreatic ductal adenocarcinomas (PDAC) that co-occur simultaneously or arise metachronously in the pancreatic parenchyma, yet their pathogenesis remains elusive. We hypothesized that two potential pathways, multicentric carcinogenesis and intrapancreatic metastasis, might contribute to forming multiple PDAC. Among 241 resected cases, we identified 20 cancer nodules from nine patients with multiple PDAC (six with synchronous PDAC, one with metachronous PDAC, and two with both synchronous and metachronous PDAC). Integrated clinical, pathological, and mutational analyses, using TP53 and SMAD4 immunostaining and targeted next-generation sequencing of 50 cancer-related genes, were conducted to examine the intertumor relationships. Four of the nine patients were assessed as having undergone multicentric carcinogenesis because of heterogeneity of immunohistochemical and/or mutation characteristics. In contrast, tumors in the other five patients showed intertumor molecular relatedness. Two of these five patients, available for matched sequencing data, showed two or more shared mutations. Moreover, all the smaller nodules in these five patients showed identical TP53 and SMAD4 expression patterns to the corresponding main tumors. Consequently, these five patients were considered to have undergone intrapancreatic metastasis. None of the five smaller nodules arising from intrapancreatic metastasis was accompanied by pancreatic intraepithelial neoplasia, and three of them were tiny (≤1mm). Patients whose tumors resulted from intrapancreatic metastasis appeared to have higher disease stages and worse outcome than those with tumors from multicentric carcinogenesis. Our results provide insight into pancreatic carcinogenesis, showing that the development of multiple PDAC involves distinct evolutionary paths that potentially affect patient prognosis.

Moderate alcohol intake promotes pancreatic ductal adenocarcinoma development in mice expressing oncogenic Kras.

Kras mutations are associated with pancreatic ductal adenocarcinoma (PDAC). Although tobacco smoking, pancreatitis, and obesity are known environmental risk factors for PDAC, the contribution of moderate alcohol intake to PDAC remains elusive. In the present study, we tested whether a combination of risk factors or moderate alcohol intake induces PDAC development in mice. Control Pdx1Cre and Pdx1Cre;LSL-KrasG12D mutant mice were fed a Western alcohol diet containing high levels of cholesterol and saturated fat, 3.5% alcohol, and lipopolysaccharide for 5 mo. In addition, mice were treated with cerulein, for induction of pancreatitis, and nicotine every month. Treatment with all of these risk factors promoted development of advanced pancreatic neoplasia and PDAC in the Pdx1Cre;LSL-KrasG12D mice but not in the control Pdx1Cre mice. Moderate alcohol intake or Western diet feeding also significantly promoted advanced neoplasia and PDAC development in Pdx1Cre;LSL-KrasG12D mice compared with mice fed a regular chow. Alcohol, but not Western diet, increased tumor development in the liver in the Pdx1Cre;LSL-KrasG12D mice, but its origin remained elusive due to leakiness of Pdx1Cre in hepatocytes. RNA-seq analysis revealed that alcohol feeding increases expression of markers for tumors (Epcam, Krt19, Prom1, Wt1, and Wwtr1), stroma (Dcn, Fn1, and Tnc), and cytokines (Tgfb1 and Tnf) and decreases expression of Fgf21 and Il6 in the pancreatic tumor tissues. Immunostaining showed heterogeneous expression of nephronectin, S100 calcium-binding protein A6, and vascular cell adhesion molecule 1 in pancreatic tumors surrounded by podoplanin-positive stromal cells. Our data indicate that moderate alcohol drinking is a risk factor for development of PDAC.NEW & NOTEWORTHY Heavy alcohol intake has been suspected to be a risk factor of pancreatic ductal adenocarcinoma (PDAC) in humans. However, the contribution of moderate alcohol intake to PDAC development remains elusive. In the present study, we experimentally show that moderate alcohol feeding significantly induces advanced stages of pancreatic intraepithelial neoplasia development and invasive PDAC in Pdx1Cre;LSL-KrasG12D mutant mice. Our data indicate that moderate alcohol drinking is a risk factor for PDAC.

Comprehensive histological evaluation with clinical analysis of venous invasion in pancreatic ductal adenocarcinoma: From histology to clinical implications.

OBJECTIVES: Venous invasion is a poor prognostic factor for pancreatic ductal adenocarcinoma (PDAC). However, our understanding of various features of venous invasion is limited. Our aim is to comprehensively evaluate various histopathologic features of venous invasion, including status, type (lymphatic or venous), number of invasion foci, and histologic pattern (pancreatic intraepithelial neoplasia [PanIN]-like, conventional) in PDACs. METHODS: Various features of venous invasion, including status, number of invasion foci, histologic patterns [pancreatic intraepithelial neoplasia (PanIN)-like, conventional], and size of involved vessels in 471 surgically resected PDACs were evaluated with all available hematoxylin and eosin (H&E)-stained slides. RESULTS: Venous invasion was observed in 319 cases (67.7%) and was more frequently associated with increased tumor size, extrapancreatic extension, resection margin involvement, diffuse tumor distribution, lymph node metastasis, and perineural invasion (all Ps < .05). High frequency (≥3 foci) of venous invasion was associated with shorter overall survival both in the entire group and in the early stage subgroup (stage I; all Ps < .05). Multivariate analysis indicated that a high frequency (≥3 foci) of venous invasion, large tumor size (>4 cm), higher histologic grade, and lymph node metastasis, were independent prognostic factors of worse overall survival (all Ps < .05). CONCLUSION: Precise evaluation of venous invasion status, including foci number of invasion, can provide additional prognostic information for patients undergoing surgical resection of PDAC, especially for those with early disease stage.

Focal parenchymal atrophy of pancreas: An important sign of underlying high-grade pancreatic intraepithelial neoplasia without invasive carcinoma, i.e., carcinoma in situ.

OBJECTIVES: Diagnosing high-grade intraepithelial neoplasia without invasion, traditionally referred to as carcinoma in situ (CIS), is essential for improving prognosis. We examined the imaging findings of patients with and without CIS to identify significant aspects for the diagnosis of CIS. METHODS: Forty-six patients strongly suspected of early pancreatic cancer without nodule on imaging (CIS group, n = 27; non-malignant group, n = 19) were retrospectively evaluated according to ten factors of computed tomography/magnetic resonance imaging (CT/MRI), endoscopic ultrasonography (EUS), and endoscopic retrograde cholangiopancreatography (ERCP) using hierarchical cluster and univariate analyses. RESULTS: Two clusters were formed by hierarchical cluster analysis. One cluster consisted of 83.3% CIS cases with similar image findings such as focal pancreatic parenchymal atrophy (FPPA) on CT/MRI, main pancreatic duct (MPD) stricture surrounded by hypoechoic areas on EUS, and MPD stricture with upstream MPD dilation on ERCP. On univariate analysis, the CIS and non-malignant groups had FPPA on CT/MRI in 15 (55.6%) and 3 (15.8%) cases (p = 0.013), and MPD stricture surrounded by hypoechoic areas on EUS in 20 (74.1%) and 4 (21.1%) cases (p = 0.001), respectively. MPD stricture surrounded by hypoechoic areas was observed in 80% (12/15) of CIS cases with FPPA on CT/MRI and correlated with FPPA. Moreover, FPPA and MPD stricture surrounded by hypoechoic areas had histopathologically observed fibrosis or fat replacement due to pancreatic parenchymal atrophy. CONCLUSIONS: FPPA and MPD stricture surrounded by hypoechoic areas are significant findings for the diagnosis of CIS.

Focal Parenchymal Atrophy and Fat Replacement Are Clues for Early Diagnosis of Pancreatic Cancer with Abnormalities of the Main Pancreatic Duct.

Pancreatic cancer is one of the most dangerous solid tumors, but its early diagnosis is difficult. The abnormality of the main pancreatic duct (MPD), such as a single localized stricture and upstream dilatation, might be useful in the early detection of pancreatic cancer. However, these findings are often observed in benign inflammatory cases. This study aimed to clarify whether early pancreatic cancer presenting MPD abnormalities has characteristic features different from those of benign cases. This is a single-center, retrospective study. We analyzed 20 patients who underwent pancreatectomy presenting with a single, localized MPD stricture without identifiable masses on imaging: 10 patients with pancreatic ductal adenocarcinoma (cancer group; 6 with stage 0 and 4 with stage I) and 10 patients with benign strictures (benign group; 8 with inflammation and 2 with low-grade pancreatic intraepithelial neoplasms). Pancreatectomy was performed in these benign cases because high-grade intraepithelial neoplasm was suspected. Although the proportion of patients with diabetes mellitus tended to be higher in the cancer group (6/10) than that in the benign group (1/10) (P = 0.058), other clinical characteristics were not different between the groups. Preoperative cytological malignancies were detected in four patients in the cancer group (4/10) but not in the benign group (P = 0.09). Focal parenchymal atrophy and fat replacement were more frequently detected on computed tomography in the cancer group (7/10) than in the benign group (1/10) (P = 0.02). In conclusion, focal parenchymal atrophy and fat replacement may provide clues for the early diagnosis of pancreatic cancer.

GABRP regulates chemokine signalling, macrophage recruitment and tumour progression in pancreatic cancer through tuning KCNN4-mediated Ca2+ signalling in a GABA-independent manner.

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis. METHODS: The Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism. RESULTS: GABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce Ca2+ entry, which leads to activation of nuclear factor κB signalling and ultimately facilitates macrophage infiltration by inducing CXCL5 and CCL20 expression. CONCLUSIONS: Overexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.

From somatic mutation to early detection: insights from molecular characterization of pancreatic cancer precursor lesions.

Pancreatic cancer arises from noninvasive precursor lesions, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasm (IPMN), and mucinous cystic neoplasm (MCN), which are curable if detected early enough. Recently, these types of precursor lesions have been extensively characterized at the molecular level, defining the timing of critical genetic alterations in tumorigenesis pathways. The results of these studies deepen our understanding of tumorigenesis in the pancreas, providing novel insights into tumor initiation and progression. Perhaps more importantly, they also provide a rational foundation for early detection approaches that could allow clinical intervention prior to malignant transformation. In this review, we summarize the results of comprehensive molecular characterization of PanINs, IPMNs, and MCNs and discuss the implications for cancer biology as well as early detection. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A case of high-grade pancreatic intraepithelial neoplasia concomitant with type 1 autoimmune pancreatitis: The process underlying both conditions.

We report a case of high-grade pancreatic intraepithelial neoplasia (PanIN) concomitant with lymphoplasmacytic sclerosing pancreatitis. The patient was an 82-year-old man in whom narrowing of the main pancreatic duct was detected incidentally by abdominal ultrasonography. Magnetic resonance cholangiopancreatography further revealed abrupt narrowing plus distal dilatation of the duct, from the pancreatic body to the tail. Distal pancreatectomy was performed under a preoperative diagnosis of intraductal papillary-mucinous neoplasm. Macroscopic examination of the surgical specimen showed an ill-demarcated, white-gray area and prominent pancreatic atrophy, while histological analysis detected small (<5 mm in diameter) cystic dilatations of the main pancreatic duct and some branch ducts plus pancreatic atrophy with fibrosis and fatty replacement of acinar cells. We also detected variously sized papillary projections, fused glands, and scattered focal papillary proliferation of columnar ductal epithelium comprising cells with elongated, mildly hyperchromatic nuclei, consistent with high-grade PanIN. In addition, we observed marked lymphoplasmacytic infiltration, periductal storiform fibrosis, and obliterative phlebitis. Immunohistochemical staining revealed abundant immunogloblin G4-positive plasma cells, indicative of type 1 autoimmune pancreatitis (AIP). The coexistence of high-grade PanIN and marked lymphoplasmacytic infiltration, typical of AIP, point to a close association between the former, as a carcinogenic process, and the latter, as an immune response.

Expression of Chosen Carcinoembryonic-Related Cell Adhesion Molecules in Pancreatic Intraepithelial Neoplasia (PanIN) Associated with Chronic Pancreatitis and Pancreatic Ductal Adenocarcinoma (PDAC).

Aims: Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) are members of the glycosylphosphatidylinositol (GPI)-linked immunoglobulin (Ig) superfamily and take part in regulation of cell adhesion, tumor suppression and angiogenesis. Overexpression of CEACAM 1, 5 and 6 is widely described in several gastrointestinal epithelial tumors. The aim of study was to evaluate the expression of CEACAM 1, CEACAM 5 and CEACAM 6 in the most common precursor lesions of pancreatic ductal adenocarcinoma -pancreatic intraepithelial neoplasia (PanIN). Methods and results: The study group consisted of 32 patients treated for chronic pancreatitis and 38 patients with pancreatic ductal adenocarcinoma who also had pancreatic intraepithelial neoplasia. The expression of CEACAM was performed by immunohistochemical method and evaluated using 3-point scale: 0 - lack of positive reaction in pancreatic intraepithelial neoplasia, 1 (weak and moderate) - reaction present in 1-30% epithelial cells in PanIN and 2 (strong) - reaction present in >30% epithelial cells in PanIN. Expression of CEACAM 1, 5 and 6 increased with increasing degree of advancement of PanIN. Differences in expression of CEACAM 1, 5 and 6 between normal pancreatic ducts and different degrees of PanIN were statistically significant (p<0.001). We observed relationship between CEACAM1 expression and localization of PanIN in different parts of the pancreas. Conclusions: CEACAM 1, CEACAM 5 and CEACAM 6 expression appears to be an early event in pancreatic carcinogenesis. Moreover, expression of CEACAM 1, 5 and 6 may represent a useful biomarker that may aid in the identification of precancerous lesions in the pancreas.