Date of Graduation

12-2025

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Wantong Yao

Committee Member

Haoqiang Ying

Committee Member

Laura Bover

Committee Member

Weiyi Peng

Committee Member

Dihua Yu

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies, with an overall 5-year survival rate of only 13%. Given the prevalence of oncogenic KRAS mutations (KRAS*) and their role in PDAC development and growth, therapeutic strategies to quench KRAS*-driven malignant progression are urgently needed to improve the clinical outcome for this disease. Our previous work identified Syndecan-1 (SDC1), a highly expressed heparan sulfate proteoglycan, as a critical downstream effector protein of KRAS*, which promotes cancer progression by mediating macropinocytosis. Moreover, SDC1 plays an essential role for the acquired resistance to KRAS* inhibition in PDAC, making it an attractive new therapeutic target, as allele-specific and pan-KRAS* inhibitors continue progressing through pre-clinical and clinical development.

However, despite the great potential of targeting SDC1 for cancer therapy, SDC1-targeted therapies have largely been explored in the context of multiple myeloma, while its potential in solid tumors is underestimated. More importantly, most of currently anti-SDC1 agents function by exploiting SDC1 as a surface target to deliver cytotoxic payload or facilitate immune cell-mediated killing, while the direct functional inhibition of SDC1 itself is frequently overlooked during the development of SDC1-targeted approaches.

To explore the potential of targeting SDC1 in solid tumors, especially in the context of pancreatic cancer, we developed a monoclonal antibody with remarkable sensitivity and specificity for human SDC1 (anti-SDC1 mAb). Anti-SDC1 mAb robustly inhibited PDAC cell proliferation in vitro and exhibited potent tumor inhibitory effects across multiple PDAC models. Mechanistically, we revealed that anti-SDC1 mAb directly inhibits macropinocytosis to block nutrient salvage as well as induces antibody-dependent cellular cytotoxicity (ADCC) to eliminate PDAC cells. Notably, in vivo, our anti-SDC1 mAb exhibited synergistic anti-tumor effects in combination with first-line chemotherapy, KRAS* inhibitors, and immunotherapies, resulting in robust tumor suppression. In summary, our findings support the anti-SDC1 mAb as a promising therapeutic strategy for PDAC and potentially other solid tumors characterized by aberrant SDC1 expression.

Keywords

Pancreatic Cancer, Therapeutic Antibody, Macropinocytosis, Syndecan-1

Download

Available for download on Saturday, December 05, 2026

Share

COinS