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.
","abstract_html":"<p>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 <em>KRAS</em> mutations (<em>KRAS*</em>) 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.</p> <p>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.</p> <p>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 <em>in vitro</em> 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, <em>in vivo</em>, 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.</p>","abstract_has_math":false,"creators":["Yang, Zecheng"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Wantong Yao","Haoqiang Ying","Laura Bover"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025-12-01T08:00:00Z","date_published":"2025-12-01T08:00:00Z","updated_at":"2026-07-24T05:50:47Z","subjects":["Pancreatic Cancer","Therapeutic Antibody","Macropinocytosis","Syndecan-1","Biotechnology","Medical Immunology","Medical Pharmacology","Translational Medical Research"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1494","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Wantong Yao","Haoqiang Ying","Laura Bover"]},{"key":"dc:creator","label":"Author","values":["Yang, Zecheng"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2026-12-05T08:00:00Z"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation (PhD)"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Pancreatic Cancer","Therapeutic Antibody","Macropinocytosis","Syndecan-1","Biotechnology","Medical Immunology","Medical Pharmacology","Translational Medical Research"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1494"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.
"]},{"key":"dc:title","label":"Title","values":["A Novel Syndecan-1 Targeted Therapeutic Antibody Inhibits Macropinocytosis and Induces Anti-Tumor Immunity in Pancreatic Cancer"]}]}],"canonical_facts":{"dc:contributor":["Wantong Yao","Haoqiang Ying","Laura Bover"],"dc:creator":["Yang, Zecheng"],"dc:date.available":["2026-12-05T08:00:00Z"],"dc:description.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.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1494"],"dc:subject":["Pancreatic Cancer","Therapeutic Antibody","Macropinocytosis","Syndecan-1","Biotechnology","Medical Immunology","Medical Pharmacology","Translational Medical Research"],"dc:title":["A Novel Syndecan-1 Targeted Therapeutic Antibody Inhibits Macropinocytosis and Induces Anti-Tumor Immunity in Pancreatic Cancer"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:50:47Z"}