Heparan Sulfate Proteoglycans in Pancreatic Ductal Adenocarcinoma (PDAC)

Advisor: Wantong Yao, MD, PhD

We have previously identified a heparan sulfate proteoglycan (HSPG), Syndecan-1 (SDC1), as a key effector for pancreatic ductal adenocarcinoma (PDAC) progression whose surface expression is driven by KRAS*. By leveraging various PDAC models, we found that surface SDC1 expression was initially diminished upon mutant KRAS (KRAS*) signaling blockade but recovered in tumor cells that bypass KRAS* dependency hence implicating its role underlying acquired resistance to KRAS* inhibition – an unresolved clinical challenge. Mechanistically, we revealed that the YAP1-SDC1 axis was the major driving force for bypassing KRAS* dependency to sustain nutrient salvage machinery, tumor maintenance and growth. Specifically, YAP1 transcriptionally regulate ARF6 GAPs in an indirect manner to promote SDC1 localization on the cell surface and sustain macropinocytosis, enhance the activation of multiple RTKs, thereby promoting resistance to KRAS*-targeted therapy. Overall, our study has provided the rationale for therapeutic targeting of the YAP-SDC1 axis to overcome resistance to KRAS* inhibition and improving the clinical outcome of patients with KRAS-mutated cancers. In the latter part of the study, we explored patterns of HS glycosaminoglycan chains attached to HSPG protein cores through HS profiling and antithrombin-Ab staining, revealing the aberrant enrichment of a unique sulfated tetrasaccharide (Tetra-1) in PDAC tissues from KRAS^G12D-driven PDAC genetically engineered mice model but not in healthy pancreas from WT-KRAS mice. HS3ST1, a gene encoding for a sulfotransferase enzyme responsible for the synthesis of Tetra-1, is significantly upregulated in PDAC tumors and dynamically altered upon KRAS* inhibition. Loss of HS3ST1 in PDAC cell lines hamper proliferation as well as colony formation, and effects were more evident in low serum conditions. This study encompasses the characterization of HS chain profiles in PDAC, opening up new avenues for the identification of novel early-detection biomarkers and functional studies of HS biosynthesis enzymes that may potentially play important roles in PDAC disease progression.

Advisory Committee:
Wantong Yao, MD, PhD, Chair
Jian Liu, PhD
Eugene Koay, MD, PhD
Anirban Maitra, MBBS
Haoqiang Ying, MD, PhD

Attend via Zoom
Meeting ID: 270 377 9140
Password: 104113