Pancreatic Neuroendocrine Tumors (PanNETs) are the most common and lethal neuroendocrine malignancies where treatments used in advanced patients have limited efficacy, adverse side effects, and acquire resistance. Thus, there is a critical need to uncover novel precision therapeutics for PanNET patients. Additionally, pre-clinical models that more accurately represent disease are an urgent necessity for translational studies.
This dissertation directly addresses these challenges by identifying histone lysine methyltransferase (KMT) NSD3 as a critical oncogenic driver of PanNETs through di-methylation of histone H3K36 (H3K36me2).
The findings shown in this body of work indicate that H3K36 methylation by NSD3 functions as a transcriptional activator accelerating tumorigenesis in PanNETs. Additionally, we established a novel genetically engineered mouse model (GEMM) for PanNETs focused on the top inactivating mutations observed in human disease. Lastly, we have identified therapeutic vulnerabilities of NSD3 that target growth-signaling pathways and bromodomain inhibition rendering tumor growth in vitro.
Together, this work elucidates the role of NSD3 in tumorigenesis and provides a rationale for this KMT as an actionable for neuroendocrine tumors.
","abstract_html":"<p>Pancreatic Neuroendocrine Tumors (PanNETs) are the most common and lethal neuroendocrine malignancies where treatments used in advanced patients have limited efficacy, adverse side effects, and acquire resistance. Thus, there is a critical need to uncover novel precision therapeutics for PanNET patients. Additionally, pre-clinical models that more accurately represent disease are an urgent necessity for translational studies.</p> <p>This dissertation directly addresses these challenges by identifying histone lysine methyltransferase (KMT) NSD3 as a critical oncogenic driver of PanNETs through di-methylation of histone H3K36 (H3K36me2).</p> <p>The findings shown in this body of work indicate that H3K36 methylation by NSD3 functions as a transcriptional activator accelerating tumorigenesis in PanNETs. Additionally, we established a novel genetically engineered mouse model (GEMM) for PanNETs focused on the top inactivating mutations observed in human disease. Lastly, we have identified therapeutic vulnerabilities of NSD3 that target growth-signaling pathways and bromodomain inhibition rendering tumor growth in vitro.</p> <p>Together, this work elucidates the role of NSD3 in tumorigenesis and provides a rationale for this KMT as an actionable for neuroendocrine tumors.</p>","abstract_has_math":false,"creators":["Fuentes, Mary Esmeralda",""],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Pawel K. Mazur, PhD","Junjie Chen, PhD","Anirban Maitra, MBBS"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-05-01T07:00:00Z","date_published":"2024-05-01T07:00:00Z","updated_at":"2026-07-24T05:49:08Z","subjects":["Mouse models of cancer","neuroendocrine tumors","epigenetics","transcriptional programming in cancer","Animal Experimentation and Research","Cancer Biology","Genetics and Genomics"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1356","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Pawel K. Mazur, PhD","Junjie Chen, PhD","Anirban Maitra, MBBS"]},{"key":"dc:creator","label":"Author","values":["Fuentes, Mary Esmeralda",""]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2025-04-26T07:00:00Z"]},{"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":["Mouse models of cancer","neuroendocrine tumors","epigenetics","transcriptional programming in cancer","Animal Experimentation and Research","Cancer Biology","Genetics and Genomics"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1356"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Pancreatic Neuroendocrine Tumors (PanNETs) are the most common and lethal neuroendocrine malignancies where treatments used in advanced patients have limited efficacy, adverse side effects, and acquire resistance. Thus, there is a critical need to uncover novel precision therapeutics for PanNET patients. Additionally, pre-clinical models that more accurately represent disease are an urgent necessity for translational studies.
This dissertation directly addresses these challenges by identifying histone lysine methyltransferase (KMT) NSD3 as a critical oncogenic driver of PanNETs through di-methylation of histone H3K36 (H3K36me2).
The findings shown in this body of work indicate that H3K36 methylation by NSD3 functions as a transcriptional activator accelerating tumorigenesis in PanNETs. Additionally, we established a novel genetically engineered mouse model (GEMM) for PanNETs focused on the top inactivating mutations observed in human disease. Lastly, we have identified therapeutic vulnerabilities of NSD3 that target growth-signaling pathways and bromodomain inhibition rendering tumor growth in vitro.
Together, this work elucidates the role of NSD3 in tumorigenesis and provides a rationale for this KMT as an actionable for neuroendocrine tumors.
"]},{"key":"dc:title","label":"Title","values":["HISTONE LYSINE METHYLTRANSFERASE NSD3 GOVERNS TRANSCRIPTIONAL PROGRAMS THAT DRIVE PANCREATIC NEUROENDOCRINE TUMORS (PANNETS)"]}]}],"canonical_facts":{"dc:contributor":["Pawel K. Mazur, PhD","Junjie Chen, PhD","Anirban Maitra, MBBS"],"dc:creator":["Fuentes, Mary Esmeralda",""],"dc:date.available":["2025-04-26T07:00:00Z"],"dc:description.abstract":["Pancreatic Neuroendocrine Tumors (PanNETs) are the most common and lethal neuroendocrine malignancies where treatments used in advanced patients have limited efficacy, adverse side effects, and acquire resistance. Thus, there is a critical need to uncover novel precision therapeutics for PanNET patients. Additionally, pre-clinical models that more accurately represent disease are an urgent necessity for translational studies.
This dissertation directly addresses these challenges by identifying histone lysine methyltransferase (KMT) NSD3 as a critical oncogenic driver of PanNETs through di-methylation of histone H3K36 (H3K36me2).
The findings shown in this body of work indicate that H3K36 methylation by NSD3 functions as a transcriptional activator accelerating tumorigenesis in PanNETs. Additionally, we established a novel genetically engineered mouse model (GEMM) for PanNETs focused on the top inactivating mutations observed in human disease. Lastly, we have identified therapeutic vulnerabilities of NSD3 that target growth-signaling pathways and bromodomain inhibition rendering tumor growth in vitro.
Together, this work elucidates the role of NSD3 in tumorigenesis and provides a rationale for this KMT as an actionable for neuroendocrine tumors.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1356"],"dc:subject":["Mouse models of cancer","neuroendocrine tumors","epigenetics","transcriptional programming in cancer","Animal Experimentation and Research","Cancer Biology","Genetics and Genomics"],"dc:title":["HISTONE LYSINE METHYLTRANSFERASE NSD3 GOVERNS TRANSCRIPTIONAL PROGRAMS THAT DRIVE PANCREATIC NEUROENDOCRINE TUMORS (PANNETS)"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:49:08Z"}