Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis largely due to inefficient diagnosis and tenacious drug resistance. Activation of pancreatic stellate cells (PSCs) and consequent development of dense stroma are prominent features accounting for this aggressive biology 1 , 2 . The reciprocal interplay between PSCs and pancreatic cancer cells (PCCs) not only enhances tumour progression and metastasis but also sustains their own activation, facilitating a vicious cycle to exacerbate tumourigenesis and drug resistance 3 – 7 . Moreover, PSC activation occurs very early during PDAC tumourigenesis 8 – 10 , and activated PSCs comprise a significant fraction of the tumour mass, providing a rich source of readily detectable factors. Therefore, we hypothesized that the communication between PSCs and PCCs could be an Achilles’ heel exploitable to develop effective strategies for PDAC therapy and diagnosis. Here, starting with systematic proteomic investigation of secreted disease mediators and underlying molecular mechanisms, we reveal that leukemia inhibitory factor (LIF) is a key paracrine factor from activated PSCs acting on cancer cells. Both pharmacologic LIF blockade and genetic Lifr deletion significantly slow tumour progression and augment chemotherapy efficacy to prolong survival of PDAC mouse models, mainly by modulating cancer cell differentiation and EMT status. Moreover, we show that, consistently in both mouse models and human PDAC, aberrant production of LIF in the pancreas is unique to pathological conditions and correlates with PDAC pathogenesis, and circulating LIF level changes correlate well with tumour response to therapy. Collectively, these findings uncover a previously unappreciated function of LIF in PDAC tumourigenesis, and suggest its translational potential as an attractive therapeutic target and circulating marker. These studies underscore how a better understanding of cell-cell communications within the tumour microenvironment promotes novel strategies for cancer therapy.

Preoperative biliary stenting and coriticosteroid use increase superficial SSI, even in patients receiving perioperative piperacillin-tazobactam. Additional measures, including extended broad-spectrum perioperative antibiotic treatment, should be considered in these patients. Organ/space SSIs appear to be related to pancreatic fistulae, which are not modifiable. Reporting these different subtypes as a single, overall rate may be misleading.

Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancerassociated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors. lysosome | autophagy | replication stress | pancreatic cancer | nucleotide metabolism P ancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death in the United States, and its incidence is increasing (1). PDAC carries a 5-y survival of less than 10%, as it is often diagnosed at a late stage and is widely refractory to available therapies. This lack of effective treatment options suggests an incomplete understanding of the biologic complexity of PDAC and mechanisms of therapeutic resistance.PDAC tumors are hypoperfused, resulting in poor nutrient delivery (2). To exist in this hostile microenvironment, PDAC cells rely on intracellular and extracellular scavenging pathways to acquire metabolic substrates for growth. Autophagy, a selfdegradative mechanism employed to recycle damaged cytosolic proteins and organelles, and macropinocytosis, the process of uptaking bulk extracellular material, are up-regulated in PDAC (3-6). As the final step of both autophagy and macropinocytosis, autophagic and endocytic cargo fuse with the lysosome, where macromolecules are degraded and substrates for metabolism are released (3, 4, 7). Inhibition of these pathways suppresses PDAC tumor growth and prolongs survival in animal models (4, 6, 8). Additionally, engaging autophagic programs confers resistance to chemoradiation in PDAC cells (9-11), and high levels of autophagy markers are correlated with worse survival in resected PDAC patients (12).The study of lysosomal function often focuses on proteolysis, which degrades misfolded proteins and damaged organelles (13,14). However, lysosomal degradation pathways also play a critical role in lipid (15-17) and nucleic acid metabolism. The recycling of nucleic ac...

Although the LN scoring in the seventh PDAC AJCC Staging System was sufficient to predict OS of our patients, more LNs than previously considered (20 vs. 15) were optimal to detect pathologic involvement. Preoperative LN detection was an accurate predictor of pN1 disease for treatment naïve patients without biliary obstruction.

In an appropriately-powered, single-institution prospective study, pasireotide was not validated as a preventive measure for pancreatic fistula.