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Background & Aims Changes in pancreatic calcium levels affect secretion and might be involved in development of chronic pancreatitis (CP). We investigated the association of CP with the transient receptor potential cation channel subfamily V member 6 gene (TRPV6), which encodes a Ca2+-selective ion channel, in an international cohort of patients and in mice. Methods We performed whole-exome DNA sequencing from a patient with idiopathic CP and from his parents, who did not have CP. We validated our findings by sequencing DNA from 300 patients with CP (not associated with alcohol consumption) and 1070 persons from the general population in Japan (control individuals). In replication studies, we sequenced DNA from patients with early-onset CP (20 years or younger) not associated with alcohol consumption from France (n = 470) and Germany (n = 410). We expressed TRPV6 variants in HEK293 cells and measured their activity using Ca2+ imaging assays. CP was induced by repeated injections of cerulein in TRPV6mut/mut mice. Results We identified the variants c.629C>T (p.A210V) and c.970G>A (p.D324N) in TRPV6 in the index patient. Variants that affected function of the TRPV6 product were found in 13 of 300 patients (4.3%) and 1 of 1070 control individuals (0.1%) from Japan (odds ratio [OR], 48.4; 95% confidence interval [CI], 6.3–371.7; P = 2.4 × 10–8). Twelve of 124 patients (9.7%) with early-onset CP had such variants. In the replication set from Europe, 18 patients with CP (2.0%) carried variants that affected the function of the TRPV6 product compared with 0 control individuals (P = 6.2 × 10–8). Variants that did not affect the function of the TRPV6 product (p.I223T and p.D324N) were overrepresented in Japanese patients vs control individuals (OR, 10.9; 95% CI, 4.5–25.9; P = 7.4 × 10–9 for p.I223T and P = .01 for p.D324N), whereas the p.L299Q was overrepresented in European patients vs control individuals (OR, 3.0; 95% CI, 1.9–4.8; P = 1.2 × 10–5). TRPV6mut/mut mice given cerulein developed more severe pancreatitis than control mice, as shown by increased levels of pancreatic enzymes, histologic alterations, and pancreatic fibrosis. Conclusions We found that patients with early-onset CP not associated with alcohol consumption carry variants in TRPV6 that affect the function of its product, perhaps by altering Ca2+ balance in pancreatic cells. TRPV6 regulates Ca2+ homeostasis and pancreatic inflammation.

in AA-depleted cells with oncogenic Kras, i.e., CAPAN-2, PANC-1 andHPDE-Kras, autophagy inhibition is without effect, and the OCR and proliferation remain significantly decreased. Thus, the non-canonical autophagy operating in cells with oncogenic Kras fails to maintain ATP production sufficient to sustain cancer cell growth in conditions of AA depletion. Conclusions: Pancreatic cells harboring oncogenic Kras lose nutrient sensitivity of the mTORC1/ULK1 pathway, and instead activate non-canonical autophagy. However, the noncanonical autophagy fails to sustain growth of nutrient-deprived PaCa cells. The results suggest AA depletion as a promising therapeutic approach in Kras-driven pancreatic cancer.

Backround: Chronic pancreatitis (CP) and pancreatic adenocarcinoma (PDAC) in humans are characterized by neural alterations, including increased neural density (ND) and hypertrophy (NH), pancreatic neuritis (PN) and neural invasion (NI) by cancer cells. The aim of his study was to evaluate the widely used PDx1-Cre/KRASG12D/Trp53R172H (KPC) genetically engineered pancreatic cancer mouse model (GEMM) regarding those features seen in human PDAC to verify this model for future research in this particular field of PDAC. Methods: Pancreatic nerve fibers in WT(n=10), ELA-hIL1 β (CP, n=10) and KPC-mice (PDAC, n= 10) were analyzed by immunohistochemical visualization of various markers, including those for sympathetic (tyrosine hydroxylase, TH) and parasympathetic (choline acetyltransferase, ChaT) quality. Myelinated sensory fibers were labeled with an antibody raised against 200 kD neurofilament H (clone RT97), thinly myelinated and unmyelinated peptidergic sensory fibers were labeled with antibodies raised against calcitonin gene-related peptide (CGRP). GAP-43 expression was used as an established marker for neuronal plasticity. The immune reactivity scores for these markers were compared to human samples of normal pancreas (NP, n=10), chronic pancreatitis (CP, n=10) and PDAC (n=10). Results: Pancreatic sympathetic was significantly reduced in murine CP and PDAC, whereas cholinergic innervation did not reveal major changes in nerves without neural invasion. Depending on the severity of neural invasion the cholinergic innervation was also decreased. Similar changes were in respective human samples. Expression pattern of GAP-43 showed an increase in enlarged nerve trunks in human as well as in murine samples. Perineural and endoneural invasion were prominent features of pancreatic cancer in both species. Conclusion: The routinely used KPC pancreatic cancer model resembles human PDAC accurately regarding neuropathic changes and neural remodeling seen in human patients. Therefore, this model is an excellent tool to further investigate the underlying interactions of cancer cells and neurons in PDAC.

Backround: Chronic pancreatitis (CP) and pancreatic adenocarcinoma (PDAC) in humans are characterized by neural alterations, including increased neural density (ND) and hypertrophy (NH), pancreatic neuritis (PN) and neural invasion (NI) by cancer cells. The aim of his study was to evaluate the widely used PDx1-Cre/KRASG12D/Trp53R172H (KPC) genetically engineered pancreatic cancer mouse model (GEMM) regarding those features seen in human PDAC to verify this model for future research in this particular field of PDAC. Methods: Pancreatic nerve fibers in WT(n=10), ELA-hIL1 β (CP, n=10) and KPC-mice (PDAC, n= 10) were analyzed by immunohistochemical visualization of various markers, including those for sympathetic (tyrosine hydroxylase, TH) and parasympathetic (choline acetyltransferase, ChaT) quality. Myelinated sensory fibers were labeled with an antibody raised against 200 kD neurofilament H (clone RT97), thinly myelinated and unmyelinated peptidergic sensory fibers were labeled with antibodies raised against calcitonin gene-related peptide (CGRP). GAP-43 expression was used as an established marker for neuronal plasticity. The immune reactivity scores for these markers were compared to human samples of normal pancreas (NP, n=10), chronic pancreatitis (CP, n=10) and PDAC (n=10). Results: Pancreatic sympathetic was significantly reduced in murine CP and PDAC, whereas cholinergic innervation did not reveal major changes in nerves without neural invasion. Depending on the severity of neural invasion the cholinergic innervation was also decreased. Similar changes were in respective human samples. Expression pattern of GAP-43 showed an increase in enlarged nerve trunks in human as well as in murine samples. Perineural and endoneural invasion were prominent features of pancreatic cancer in both species. Conclusion: The routinely used KPC pancreatic cancer model resembles human PDAC accurately regarding neuropathic changes and neural remodeling seen in human patients. Therefore, this model is an excellent tool to further investigate the underlying interactions of cancer cells and neurons in PDAC.