Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression.

The melanoma-associated antigen family A (MAGEA) antigens are expressed in a wide variety of malignant tumors but not in adult somatic cells, rendering them attractive targets for cancer immunotherapy. Here we show that a number of cancer-associated MAGEA mutants that undergo proteasome-dependent degradation in vitro could negatively impact their utility as immunotherapeutic targets. Importantly, in pancreatic ductal adenocarcinoma cell models, MAGEA6 suppresses macroautophagy (autophagy). The inhibition of autophagy is released upon MAGEA6 degradation, which can be induced by nutrient deficiency or by acquisition of cancer-associated mutations. Using xenograft mouse models, we demonstrated that inhibition of autophagy is critical for tumor initiation whereas reinstitution of autophagy as a consequence of MAGEA6 degradation contributes to tumor progression. These findings could inform cancer immunotherapeutic strategies for targeting MAGEA antigens and provide mechanistic insight into the divergent roles of MAGEA6 during pancreatic cancer initiation and progression.

Pancreatic Incidentalomas: A Management Algorithm for Identifying Ectopic Spleens.

BACKGROUND: Identification of incidental pancreatic lesions is increasing because of advancements in imaging. Diagnosis remains a challenge for clinicians, with intrapancreatic accessory spleens (IPAS) posing a unique dilemma. IPAS are frequently resected because of inability to exclude alternate diagnoses, subjecting patients to unnecessary risk. The purpose of this study was to examine our institutional experience with IPAS and develop a multidisciplinary algorithm to improve preoperative diagnosis. MATERIALS AND METHODS: Patients who underwent a distal pancreatectomy at a single institution from 2005 to 2018 were identified from a prospectively maintained database. Examination of final pathology for a diagnosis of IPAS yielded the final cohort. Demographics, preoperative workup, and operative course were reviewed and analyzed. A diagnostic algorithm was composed based on the consensus of a panel of expert pancreatic surgeons, a radiologist, and a pathologist. RESULTS: Ten patients of 303 patients who underwent a distal pancreatectomy were identified with a final pathology of IPAS. The average age was 54 y, 80% were white, and 60% were male. Lesions ranged in size from 7 mm to 5.1 cm in largest diameter (mean 2.2 cm). Lesions were described as round, well-marginated, and enhancing masses within the pancreatic tail. Preoperative workup was variable in terms of imaging and laboratory testing. Diagnostic workups were examined and combined with multidisciplinary input to create a diagnostic algorithm. CONCLUSIONS: Incidental pancreatic lesions like IPAS remain a diagnostic challenge for clinicians. Employing a diagnostic algorithm as proposed may aid in the distinction of malignant and premalignant pathology and prevent unwarranted pancreatic resections.

Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer.

Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in The Cancer Genome Atlas datasets. In addition to confirming oncogenic activity of the known fusion oncogenes engineered by our construction strategy, we validated five novel fusion genes involving MET, NTRK2, and BRAF kinases that exhibited potent transforming activity and conferred sensitivity to FDA-approved kinase inhibitors. Our fusion construction strategy also enabled domain-function studies of BRAF fusion genes. Our results confirmed other reports that the transforming activity of BRAF fusions results from truncation-mediated loss of inhibitory domains within the N-terminus of the BRAF protein. BRAF mutations residing within this inhibitory region may provide a means for BRAF activation in cancer, therefore we leveraged the modular design of our fusion gene construction methodology to screen N-terminal domain mutations discovered in tumors that are wild-type at the BRAF mutation hotspot, V600. We identified an oncogenic mutation, F247L, whose expression robustly activated the MAPK pathway and sensitized cells to BRAF and MEK inhibitors. When applied broadly, these tools will facilitate rapid fusion gene construction for subsequent functional characterization and translation into personalized treatment strategies. Cancer Res; 77(13); 3502-12. ©2017 AACR.

Pancreatic endometrial cyst mimics mucinous cystic neoplasm of the pancreas.

Pancreatic cysts include a variety of benign, premalignant, and malignant lesions. Endometrial cysts in the pancreas are exceedingly rare lesions that are difficult to diagnose pre-operatively. This report describes the findings in a 43-year-old patient with a recent episode of acute pancreatitis who presented with a large cyst in the tail of the pancreas. Imaging demonstrated a loculated pancreatic cyst, and cyst fluid aspiration revealed an elevated amylase and carcinoembryonic antigen. The patient experienced an interval worsening of abdominal pain, fatigue, diarrhea, and a 15-pound weight loss 3 mo after the initial episode of pancreatitis. With concern for a possible pre-malignant lesion, the patient underwent a laparoscopic distal pancreatectomy with splenectomy, which revealed a 16 cm × 12 cm × 4 cm lesion. Final histopathology was consistent with an intra-pancreatic endometrial cyst. Here we discuss the overlapping imaging and laboratory features of pancreatic endometrial cysts and mucinous cystic neoplasms of the pancreas.