Requirement of Sterol Regulatory Element‐Binding Protein Pathway in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with limited diagnostic and therapeutic options. Due to its proliferative nature, PDAC tumor cells have a high demand for lipid synthesis. However, this tumor is known to be poorly vascularized and nestled within a hypoxic environment. As lipid synthesis is a highly oxygen‐consumptive process, neoplastic cells are challenged with meeting the demand for lipids. Cells, including cancer cells, respond to lipid conditions through sterol regulatory element‐binding proteins (SREBPs). SREBPs are master regulators of lipid homeostasis and require SREBP cleavage activating protein (SCAP) during signaling to regulate lipid synthesis. While the SREBP pathway has been implicated in several cancers, its role in PDAC has not been examined. Here, we acquired four patient‐derived pancreatic adenocarcinoma cell lines, knocked out SCAP, then followed with a rescue. We performed functional growth assays using both lipid‐poor and lipid‐rich conditions as well as subcutaneous and orthotopic xenografts in nude mice. In lipid‐poor conditions, SCAP knockout cells showed significantly reduced growth when compared to wildtype or SCAP rescued cells. In subcutaneous tumor xenografts, SCAP knockout cells exhibited reduced tumor volume in 3 out of 4 cell lines when compared to parent wildtype tumor cells. Similarly, SCAP knockout cells grew poorly in pancreatic orthotopic xenograft models. Our results demonstrate that loss of SCAP in PDAC tumor cells alters growth both in vitro and in vivo. These findings suggest SCAP may be useful as a therapeutic target in combating PDAC.Support or Funding InformationNIH T32 OD011089 (SM); Allegheny Health Network Cancer Grant (PJE); Sol Goldman Pancreatic Cancer Research Center Grant from Sidney Kimmel Comprehensive Center (PJE); NIH F31LB131185 (MM)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.