Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells
Summary: Malignancy is enabled by pro-growth mutations and adequate energy provision. However, global metabolic activation would be self-terminating if it depleted tumor resources. Cancer cells could avoid this by rationing resources, e.g., dynamically switching between “baseline” and “activated” me...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723016248 |
| _version_ | 1797377842759073792 |
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| author | Wiktoria Blaszczak Bobby White Stefania Monterisi Pawel Swietach |
| author_facet | Wiktoria Blaszczak Bobby White Stefania Monterisi Pawel Swietach |
| author_sort | Wiktoria Blaszczak |
| collection | DOAJ |
| description | Summary: Malignancy is enabled by pro-growth mutations and adequate energy provision. However, global metabolic activation would be self-terminating if it depleted tumor resources. Cancer cells could avoid this by rationing resources, e.g., dynamically switching between “baseline” and “activated” metabolic states. Using single-cell metabolic phenotyping of pancreatic ductal adenocarcinoma cells, we identify MIA-PaCa-2 as having broad heterogeneity of fermentative metabolism. Sorting by a readout of lactic acid permeability separates cells by fermentative and respiratory rates. Contrasting phenotypes persist for 4 days and are unrelated to cell cycling or glycolytic/respiratory gene expression; however, transcriptomics links metabolically active cells with interleukin-6 receptor (IL-6R)-STAT3 signaling. We verify this by IL-6R/STAT3 knockdowns and sorting by IL-6R status. IL-6R/STAT3 activates fermentation and transcription of its inhibitor, SOCS3, resulting in delayed negative feedback that underpins transitions between metabolic states. Among cells manifesting wide metabolic heterogeneity, dynamic IL-6R/STAT3 signaling may allow cell cohorts to take turns in progressing energy-intense processes without depleting shared resources. |
| first_indexed | 2024-03-08T19:59:11Z |
| format | Article |
| id | doaj.art-719b9f92f76949c4ac5e60ab238e5b03 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-08T19:59:11Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-719b9f92f76949c4ac5e60ab238e5b032023-12-24T04:45:25ZengElsevierCell Reports2211-12472024-01-01431113612Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cellsWiktoria Blaszczak0Bobby White1Stefania Monterisi2Pawel Swietach3Department of Physiology, Anatomy & Genetics, University of Oxford, Sherrington Building, Parks Road, OX1 3PT Oxford, UKDepartment of Physiology, Anatomy & Genetics, University of Oxford, Sherrington Building, Parks Road, OX1 3PT Oxford, UKDepartment of Physiology, Anatomy & Genetics, University of Oxford, Sherrington Building, Parks Road, OX1 3PT Oxford, UKDepartment of Physiology, Anatomy & Genetics, University of Oxford, Sherrington Building, Parks Road, OX1 3PT Oxford, UK; Corresponding authorSummary: Malignancy is enabled by pro-growth mutations and adequate energy provision. However, global metabolic activation would be self-terminating if it depleted tumor resources. Cancer cells could avoid this by rationing resources, e.g., dynamically switching between “baseline” and “activated” metabolic states. Using single-cell metabolic phenotyping of pancreatic ductal adenocarcinoma cells, we identify MIA-PaCa-2 as having broad heterogeneity of fermentative metabolism. Sorting by a readout of lactic acid permeability separates cells by fermentative and respiratory rates. Contrasting phenotypes persist for 4 days and are unrelated to cell cycling or glycolytic/respiratory gene expression; however, transcriptomics links metabolically active cells with interleukin-6 receptor (IL-6R)-STAT3 signaling. We verify this by IL-6R/STAT3 knockdowns and sorting by IL-6R status. IL-6R/STAT3 activates fermentation and transcription of its inhibitor, SOCS3, resulting in delayed negative feedback that underpins transitions between metabolic states. Among cells manifesting wide metabolic heterogeneity, dynamic IL-6R/STAT3 signaling may allow cell cohorts to take turns in progressing energy-intense processes without depleting shared resources.http://www.sciencedirect.com/science/article/pii/S2211124723016248CP: MetabolismCP: Cancer |
| spellingShingle | Wiktoria Blaszczak Bobby White Stefania Monterisi Pawel Swietach Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells Cell Reports CP: Metabolism CP: Cancer |
| title | Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells |
| title_full | Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells |
| title_fullStr | Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells |
| title_full_unstemmed | Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells |
| title_short | Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells |
| title_sort | dynamic il 6r stat3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells |
| topic | CP: Metabolism CP: Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723016248 |
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