Abstract 4092: Glycosyltransferase ST6Gal-I promotes pancreatic ductal adenocarcinoma progression and metastasis
Authors: Chakraborty Asmi , Jones Robert B. , Klug Christopher A. , Smythies Lesley E. , Bellis Susan L. 
Published: August 2018

Sialyltransferase ST6Gal-I adds α2-6 sialic acids to select N-glycosylated cell surface receptors, thereby modulating receptor function and intracellular signaling. ST6Gal-I is upregulated in multiple human cancers, including &gt;70% of pancreatic ductal adenocarcinoma (PDAC) samples. ST6Gal-I confers cancer stem cell (CSC) properties evidenced by tumorspheroid growth, chemoresistance and tumor initiating potential. As an example, we previously reported that ST6Gal-I imparts gemcitabine resistance by dampening DNA damage. One possible mechanism by which ST6Gal-I promotes a CSC phenotype is by increasing the expression of the master stem cell transcription factor, Sox-9. Forced overexpression or knockdown of ST6Gal-I directly regulates Sox9 expression in a wide array of established cancer lines. Sox9 is known to be a potent driver of acinar to ductal metaplasia (ADM), a key PDAC initiating event. To interrogate the role of ST6Gal-I and Sox9 in ADM, ST6Gal-I was overexpressed in the nontransformed acinar cell line, 266-6. ST6Gal-I overexpression was found to induce expression of Sox9 and other ductal markers. Furthermore, ST6Gal-I overexpressing cells spontaneously formed foci in adherent culture, a hallmark of malignant transformation. Contrarily, ST6Gal-I knockdown in 266-6 cells decreased cell viability. Post ADM, PDAC progresses through the formation of PanINs. This process of progressive lesion formation leading to frank PDAC can be replicated in murine models of pancreatic cancer utilizing pancreas specific oncogenic K-Ras (KC). To investigate the role of ST6Gal-I pertaining to PDAC in vivo we generated ST6Gal-I knock-in (KI) mice with oncogenic K-Ras (KC-ST6Gal-I KI). The KC-ST6Gal-I KI mice presented with significantly decreased overall survival (median = 4.3 months) compared to the KC mice (median = 14 months). This was coupled with a marked increase in liver and lung metastasis in KC-ST6Gal-I KI mice compared to KC mice. To better understand the molecular events underlying ST6Gal-I's PDAC-promoting function, we generated organoids from KC, KC-ST6Gal-I KI, ST6Gal-I KI and WT mice. Preliminary data indicate that there is increased Sox-9 expression in ST6Gal-I KI organoids compared to WT controls. As well, the number of organoids formed in culture is increased in ST6Gal-I KI mice compared to the control. Since organoids are derived from the resident stem cells, this data further indicates increased stemness with enhanced ST6Gal-I expression. In ongoing studies we are defining the signaling mechanisms underpinning a ST6Gal-I/Sox9 axis in PDAC initiation events and other aspects of CSC behavior. These collective studies highlight a novel role for tumor glycans in PDAC pathogenesis, and implicate ST6Gal-I as a promising therapeutic target.

Citation Format: Asmi Chakraborty, Robert B. Jones, Christopher A. Klug, Lesley E. Smythies, Susan L. Bellis. Glycosyltransferase ST6Gal-I promotes pancreatic ductal adenocarcinoma progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4092.