Abstract C31: The glycosaminoglycan syndecan-4 facilitates pancreatic cancer progression and biologic aggressiveness

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a treatment-recalcitrant malignancy that harbors several key driver mutations at a high frequency (e.g., KRAS, TP53, CDKN2A, and SMAD4<), as well numerous driver mutations that occur at a relatively low and variable frequency among patients with PDAC. Heparan-sulfate proteoglycans (HSPGs) constitute a large family of glycanated proteins that modulate numerous cellular processes and interact with components of the extracellular matrix (ECM) and with heparin-binding growth factors such as heparin binding EGF-like growth factor (HBEGF) that activates the EGF receptor (EGFR) and transforming growth factor beta (TGF-beta) moieties. Syndecan-4 (SDC4) is a transmembrane HSPG that has critical roles in focal adhesion formation, cytoskeletal attachment, cell contractility and motility, and cell signaling, especially in relation to pathways activated by heparin-binding growth factors. To date, the role of SDC4 in PDAC has not been clearly elucidated. Yet, data from 1,034 PDAC samples in The Cancer Genome Atlas (TCGA) revealed that 19% of these samples exhibited altered SDC4 expression, a majority of which were either gain-of-function or amplification alterations often co-occurring with enhanced TGF-beta1 expression, thus underscoring the potential importance of SDC4 in PDAC. Given that TGF-beta1 increases SDC4 expression whereas SDC4 modulates TGF-beta1 actions and interacts with EGFR, we sought to test the hypothesis that SDC4 contributes to PDAC’s progression. Accordingly, we established a novel genetically engineered mouse model (GEMM) of PDAC in which pancreas-specific Cre-mediated expression of oncogenic Kras was combined with deletion of a conditional Ink4a/Arf allele in the presence or absence of SDC4: Pdx1-Cre;LSL-KrasG12D;Ink4a/Arflox/lox;Sdc4-/-, termed KIS4-/-C mice. By comparison with control KIS4 animals, KIS4-/-C mice exhibited attenuated pancreatic tumor growth and markedly prolonged survival. There was attenuation of cancer cell proliferation in the tumors, as determined by Ki67 staining, as well as decreased desmoplasia as evidenced by Mason trichrome staining. By contrast, KIS4+/-C animals with heterozygous loss of SDC4 only exhibited a modest survival advantage by comparison with control KIS4 animals. Taken together, these findings suggest that strategies based on suppressing SDC4 expression and/or function may yield new therapeutic approaches in PDAC. (Supported in part by National Cancer Institute grant CA-075059 to M.K.) Citation Format: Samantha McElyea, Murray Korc. The glycosaminoglycan syndecan-4 facilitates pancreatic cancer progression and biologic aggressiveness [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C31.