Date Published: March 21, 2019
Publisher: Public Library of Science
Author(s): Megha Singhal, Mahsa Khatibeghdami, Daniel R. Principe, Georgina E. Mancinelli, Kyle M. Schachtschneider, Lawrence B. Schook, Paul J. Grippo, Sam R. Grimaldo, Aamir Ahmad.
Current therapies for pancreatic ductal adenocarcinoma (PDAC) only modestly impact survival and can be highly toxic. A greater understanding of the molecules regulating this disease is critical for identifying new drug targets and developing more effective therapies. The L6 family of proteins are known to be positive regulators of tumor growth and metastasis among various cancers. However, little is known about the L6 family member TM4SF18. We investigated the expression and localization of the TM4SF18 protein in normal human pancreas and in PDAC tissue. Utilizing immunohistochemistry (IHC) and western blot analysis, our studies for the first time demonstrate that TM4SF18 is highly expressed in PDAC tumor epithelium. Furthermore, we identified TM4SF18 to be expressed in normal acinar tissue and weakly expressed in normal ducts. Although there is minimal expression in normal ducts, we observed increased TM4SF18 levels in preneoplastic ducts and tumor epithelium. To investigate a functional role of TM4SF18 in PDAC we developed stably-expressing inducible shRNA pancreatic cancer cell lines. Knockdown of the TM4SF18 protein led to a significant decrease in Capan-1 cell growth as measured by the MTT assay, demonstrating this molecule to be a novel regulator of PDAC. Uniquely there is no ortholog of the TM4SF18 gene in mouse or rat prompting us to seek other in vivo experimental models. Using IHC and western blot analysis, expression of TM4SF18 was confirmed in the porcine PDAC model, thus we establish an alternative model to investigate this gene. TM4SF18 represents a promising novel biomarker and therapeutic target for pancreatic cancer.
Pancreatic ductal adenocarcinoma cancer (PDAC) is one of the deadliest cancers predicted to be the second-largest cause of cancer-related death by 2020 . Currently the five-year survival rate is at 9% mainly due to poor detection methods and lack of therapeutic options . There is an urgent need to identify new therapeutic and diagnostic markers to help extend patient survival and reduce disease-associated morbidity.
All animal work was conducted according to relevant national and international guidelines. All animal studies and procedures were approved by The University of Illinois Institutional Animal Care and Use Committee (IACUC; Protocol numbers 11221 for pig).
In summary, to our knowledge we provide the first evidence that TM4SF18 is expressed in normal and pancreatic cancer tissue including acinar tissue, pre-neoplastic ductal lesions, and tumor epithelium. In addition, we define a regulatory role of TM4SF18 in pancreatic cancer cell growth. Lastly, we identified the porcine PDAC model as a platform for future investigations into this promising new target for pancreatic cancer.