Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells
| العنوان: | Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells |
|---|---|
| المؤلفون: | Christopher J. Halbrook, Galloway Thurston, Seth Boyer, Cecily Anaraki, Jennifer A. Jiménez, Amy McCarthy, Nina G. Steele, Samuel A. Kerk, Hanna S. Hong, Lin Lin, Fiona V. Law, Catherine Felton, Lorenzo Scipioni, Peter Sajjakulnukit, Anthony Andren, Alica K. Beutel, Rima Singh, Barbara S. Nelson, Fran Van Den Bergh, Abigail S. Krall, Peter J. Mullen, Li Zhang, Sandeep Batra, Jennifer P. Morton, Ben Z. Stanger, Heather R. Christofk, Michelle A. Digman, Daniel A. Beard, Andrea Viale, Ji Zhang, Howard C. Crawford, Marina Pasca di Magliano, Claus Jorgensen, Costas A. Lyssiotis |
| المصدر: | Nature cancer, vol 3, iss 11 Nature Cancer |
| بيانات النشر: | Springer Science and Business Media LLC, 2022. |
| سنة النشر: | 2022 |
| مصطلحات موضوعية: | Cancer Research, Adenocarcinoma, Pancreatic Neoplasms, Pancreatic Cancer, Mice, Rare Diseases, Oncology, Tumor Microenvironment, 2.1 Biological and endogenous factors, Animals, Humans, Aetiology, Asparagine, Digestive Diseases, Symbiosis, Nutrition, Cancer |
| الوصف: | The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG–asparaginase sensitizes tumors to mitochondrial targeting with phenformin. |
| وصف الملف: | application/pdf |
| تدمد: | 2662-1347 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::97d1d8ab8d7e4958d9992ca11db28b89Test https://doi.org/10.1038/s43018-022-00463-1Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....97d1d8ab8d7e4958d9992ca11db28b89 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 26621347 |
|---|