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Anaraki, Cecily; Thurston, Galloway; Steele, Nina G.; Kerk, Samuel A.; Hong, Hanna; Sajjakulnukit, Peter; Andren, Anthony; Felton, Catherine; Beutel, Alica; Singh, Rima; Christofk, Heather R.; Viale, Andrea; Crawford, Howard; di Magliano, Marina Pasca; Jorgensen, Claus; Lyssiotis, Costas A.; Halbrook, Christopher J.

Abstract B012: Differential stress responses drive asparagine exchange in pancreatic cancer

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  • Medientyp: E-Artikel
  • Titel: Abstract B012: Differential stress responses drive asparagine exchange in pancreatic cancer
  • Beteiligte: Anaraki, Cecily; Thurston, Galloway; Steele, Nina G.; Kerk, Samuel A.; Hong, Hanna; Sajjakulnukit, Peter; Andren, Anthony; Felton, Catherine; Beutel, Alica; Singh, Rima; Christofk, Heather R.; Viale, Andrea; Crawford, Howard; di Magliano, Marina Pasca; Jorgensen, Claus; Lyssiotis, Costas A.; Halbrook, Christopher J.
  • Erschienen: American Association for Cancer Research (AACR), 2022
  • Erschienen in: Cancer Research
  • Sprache: Englisch
  • DOI: 10.1158/1538-7445.panca22-b012
  • ISSN: 1538-7445
  • Schlagwörter: Cancer Research ; Oncology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:p>Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States, contrasting a relatively low incidence rate. A principal barrier to the treatment of pancreatic cancer is the densely fibrotic tumor microenvironment and the high interstitial pressure which acts to collapse blood vessels, impairing the delivery of chemotherapy. This lack of functional vasculature limits nutrient availability within the tumor, causing cancer cells to develop numerous metabolic adaptations to allow for proliferation in hypoxic, austere conditions. Recent studies have demonstrated several clonal behaviors of cancer cells within individual pancreatic tumors, although it is unclear if this is true of metabolism. Exploring this, we found the metabolic profiles and sensitivities of a series of clonal cell lines derived from a single pancreatic tumor clustered into two distinct groups. These groups demonstrated differential sensitivities to inhibitors of mitochondrial metabolism; whereby the growth of the sensitive clones during impaired respiration can be rescued through co-culture with the insensitive cells. Profiling metabolites exchanged by the clonal populations, we identified this is mediated by asparagine released by insensitive cells. Mechanistically, the production of asparagine is driven by differential stress response pathway activation between clones. We further determined that exogenous asparagine supports the growth of both cancer and non-cancerous cells during limited respiration. Conversely, we found that the use of asparaginase to degrade asparagine sensitizes PDA tumors to mitochondrial inhibition. Collectively these data demonstrate distinct metabolic classes of cancer cells within single tumors and identify asparagine as a potential target to sensitize tumors to mitochondrial inhibition.</jats:p> <jats:p>Citation Format: Cecily Anaraki, Galloway Thurston, Nina G. Steele, Samuel A. Kerk, Hanna Hong, Peter Sajjakulnukit, Anthony Andren, Catherine Felton, Alica Beutel, Rima Singh, Heather R. Christofk, Andrea Viale, Howard Crawford, Marina Pasca di Magliano, Claus Jorgensen, Costas A. Lyssiotis, Christopher J. Halbrook. Differential stress responses drive asparagine exchange in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B012.</jats:p>
  • Zugangsstatus: Freier Zugang