Multiomics Analysis of Spatially Distinct Stromal Cells Reveals Tumor-Induced O-Glycosylation of the CDK4–pRB Axis in Fibroblasts at the Invasive Tumor Edge
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- Gina Bouchard
- 1Department of Biomedical Data Science, Stanford University, Stanford, California.
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- Fernando Jose Garcia-Marques
- 2Department of Radiology, Canary Center for Cancer Early Detection, Palo Alto, California.
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- Loukia Georgiou Karacosta
- 1Department of Biomedical Data Science, Stanford University, Stanford, California.
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- Weiruo Zhang
- 1Department of Biomedical Data Science, Stanford University, Stanford, California.
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- Abel Bermudez
- 2Department of Radiology, Canary Center for Cancer Early Detection, Palo Alto, California.
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- Nicholas McIlvain Riley
- 4Departments of Chemistry, Stanford University, Stanford, California.
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- Sushama Varma
- 5Department of Pathology, Stanford University, Stanford, California.
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- Lindsey Catherine Mehl
- 1Department of Biomedical Data Science, Stanford University, Stanford, California.
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- Jalen Anthony Benson
- 6Department of Cardiothoracic Surgery, Stanford University, Stanford, California.
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- Joseph B. Shrager
- 6Department of Cardiothoracic Surgery, Stanford University, Stanford, California.
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- Carolyn Ruth Bertozzi
- 4Departments of Chemistry, Stanford University, Stanford, California.
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- Sharon J. Pitteri
- 2Department of Radiology, Canary Center for Cancer Early Detection, Palo Alto, California.
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- Amato J. Giaccia
- 3Department of Radiation Oncology, Stanford University, Stanford, California.
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- Sylvia Katina Plevritis
- 1Department of Biomedical Data Science, Stanford University, Stanford, California.
抄録
<jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>The invasive leading edge represents a potential gateway for tumor metastasis. The role of fibroblasts from the tumor edge in promoting cancer invasion and metastasis has not been comprehensively elucidated. We hypothesize that cross-talk between tumor and stromal cells within the tumor microenvironment results in activation of key biological pathways depending on their position in the tumor (edge vs. core). Here we highlight phenotypic differences between tumor-adjacent-fibroblasts (TAF) from the invasive edge and tumor core fibroblasts from the tumor core, established from human lung adenocarcinomas. A multiomics approach that includes genomics, proteomics, and O-glycoproteomics was used to characterize cross-talk between TAFs and cancer cells. These analyses showed that O-glycosylation, an essential posttranslational modification resulting from sugar metabolism, alters key biological pathways including the cyclin-dependent kinase 4 (CDK4) and phosphorylated retinoblastoma protein axis in the stroma and indirectly modulates proinvasive features of cancer cells. In summary, the O-glycoproteome represents a new consideration for important biological processes involved in tumor–stroma cross-talk and a potential avenue to improve the anticancer efficacy of CDK4 inhibitors.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>A multiomics analysis of spatially distinct fibroblasts establishes the importance of the stromal O-glycoproteome in tumor–stroma interactions at the leading edge and provides potential strategies to improve cancer treatment.</jats:p> <jats:p>See related commentary by De Wever, p. 537</jats:p> </jats:sec>
収録刊行物
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- Cancer Research
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Cancer Research 82 (4), 648-664, 2021-12-01
American Association for Cancer Research (AACR)
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詳細情報 詳細情報について
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- CRID
- 1360298761627316864
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- ISSN
- 15387445
- 00085472
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- データソース種別
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- Crossref