{"id":{"repo_id":"nus","oai_identifier":"oai:scholarbank.nus.edu.sg:10635/224478"},"canonical_url":"https://search.dev.ndltd.org/etd/nus/oai:scholarbank.nus.edu.sg:10635/224478","repository":{"repo_id":"nus","name":"National University of Singapore","base_url":"https://scholarbank.nus.edu.sg/oai/request"},"display":{"title":"PROGRAMMED ADDICTION OF PANCREATIC CANCER TO NUCLEOTIDE METABOLISM BY THE TUMOR MICROENVIRONMENT","abstract":"Pancreatic ductal adenocarcinoma (PDAC) is one of the fastest growing malignancy, yet PDAC cells face a harsh tumor microenvironment (TME) of poor nutrient availability. To adapt, they were shown to exploit stellate cells, the predominant stromal cells, for growth-promoting nutrients. However, there is inadequate understanding of tumor-stellate cells crosstalks in sustaining nucleotide synthesis – a substrate and energy-intensive process. Using patient-derived co-cultured models that closely recapitulated PDAC histology, KRAS genotype and gemcitabine response, I uncover that stellate cells strategized nutrient sharing and partitioning of nucleotide substrates to fuel PDAC growth. By reducing environmental folic acid, this decreases folic acid-responsive TYMS and drives PDAC cells to salvage stellate-derived thymidine. Corroboratively, stellate cells provide aspartate through SLC1A3-mediated uptake in PDAC cells and this enhances GMP synthesis. My findings highlight the need to limit stellate-supplied nutrients in future therapeutic design for PDAC.","abstract_html":"Pancreatic ductal adenocarcinoma (PDAC) is one of the fastest growing malignancy, yet PDAC cells face a harsh tumor microenvironment (TME) of poor nutrient availability. To adapt, they were shown to exploit stellate cells, the predominant stromal cells, for growth-promoting nutrients. However, there is inadequate understanding of tumor-stellate cells crosstalks in sustaining nucleotide synthesis – a substrate and energy-intensive process. Using patient-derived co-cultured models that closely recapitulated PDAC histology, KRAS genotype and gemcitabine response, I uncover that stellate cells strategized nutrient sharing and partitioning of nucleotide substrates to fuel PDAC growth. By reducing environmental folic acid, this decreases folic acid-responsive TYMS and drives PDAC cells to salvage stellate-derived thymidine. Corroboratively, stellate cells provide aspartate through SLC1A3-mediated uptake in PDAC cells and this enhances GMP synthesis. My findings highlight the need to limit stellate-supplied nutrients in future therapeutic design for PDAC.","abstract_has_math":false,"creators":["SHIRLEY LAM"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2021,"date_issued":"2021-12-27","date_published":"2021-12-27","updated_at":"2026-07-24T03:31:38Z","subjects":["Pancreatic cancer, Tumor-stellate crosstalk, Nucleotide synthesis"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["SHIRLEY LAM"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2021-12-27"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://scholarbank.nus.edu.sg/handle/10635/224478"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Pancreatic cancer, Tumor-stellate crosstalk, Nucleotide synthesis"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://scholarbank.nus.edu.sg/bitstreams/d6f880b0-19c8-4440-8e2e-fac9d72e1506/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Pancreatic ductal adenocarcinoma (PDAC) is one of the fastest growing malignancy, yet PDAC cells face a harsh tumor microenvironment (TME) of poor nutrient availability. To adapt, they were shown to exploit stellate cells, the predominant stromal cells, for growth-promoting nutrients. However, there is inadequate understanding of tumor-stellate cells crosstalks in sustaining nucleotide synthesis – a substrate and energy-intensive process. Using patient-derived co-cultured models that closely recapitulated PDAC histology, KRAS genotype and gemcitabine response, I uncover that stellate cells strategized nutrient sharing and partitioning of nucleotide substrates to fuel PDAC growth. By reducing environmental folic acid, this decreases folic acid-responsive TYMS and drives PDAC cells to salvage stellate-derived thymidine. Corroboratively, stellate cells provide aspartate through SLC1A3-mediated uptake in PDAC cells and this enhances GMP synthesis. My findings highlight the need to limit stellate-supplied nutrients in future therapeutic design for PDAC."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["5adc15c2de9b6ab9ad44f64a8c0feb1c","90ec2545742cd1d004eb4d77ccc0b435"]},{"key":"dc:title","label":"Title","values":["PROGRAMMED ADDICTION OF PANCREATIC CANCER TO NUCLEOTIDE METABOLISM BY THE TUMOR MICROENVIRONMENT"]}]}],"canonical_facts":{"dc:creator":["SHIRLEY LAM"],"dc:date.issued":["2021-12-27"],"dc:description.abstract":["Pancreatic ductal adenocarcinoma (PDAC) is one of the fastest growing malignancy, yet PDAC cells face a harsh tumor microenvironment (TME) of poor nutrient availability. To adapt, they were shown to exploit stellate cells, the predominant stromal cells, for growth-promoting nutrients. However, there is inadequate understanding of tumor-stellate cells crosstalks in sustaining nucleotide synthesis – a substrate and energy-intensive process. Using patient-derived co-cultured models that closely recapitulated PDAC histology, KRAS genotype and gemcitabine response, I uncover that stellate cells strategized nutrient sharing and partitioning of nucleotide substrates to fuel PDAC growth. By reducing environmental folic acid, this decreases folic acid-responsive TYMS and drives PDAC cells to salvage stellate-derived thymidine. Corroboratively, stellate cells provide aspartate through SLC1A3-mediated uptake in PDAC cells and this enhances GMP synthesis. My findings highlight the need to limit stellate-supplied nutrients in future therapeutic design for PDAC."],"dc:format.checksum.md5":["5adc15c2de9b6ab9ad44f64a8c0feb1c","90ec2545742cd1d004eb4d77ccc0b435"],"dc:identifier.uri":["https://scholarbank.nus.edu.sg/bitstreams/d6f880b0-19c8-4440-8e2e-fac9d72e1506/download"],"dc:relation.isreferencedby":["https://scholarbank.nus.edu.sg/handle/10635/224478"],"dc:subject":["Pancreatic cancer, Tumor-stellate crosstalk, Nucleotide synthesis"],"dc:title":["PROGRAMMED ADDICTION OF PANCREATIC CANCER TO NUCLEOTIDE METABOLISM BY THE TUMOR MICROENVIRONMENT"],"dc:type":["Thesis"]},"updated_at":"2026-07-24T03:31:38Z"}