Article ; Online: Multiomics Analysis of Spatially Distinct Stromal Cells Reveals Tumor-Induced O-Glycosylation of the CDK4-pRB Axis in Fibroblasts at the Invasive Tumor Edge.
2022 Volume 82, Issue 4, Page(s) 648–664
Abstract: 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 ... ...
| Abstract | 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. Significance: 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. See related commentary by De Wever, p. 537. |
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| MeSH term(s) | A549 Cells ; Cancer-Associated Fibroblasts/metabolism ; Cell Line, Tumor ; Cyclin-Dependent Kinase 4/genetics ; Cyclin-Dependent Kinase 4/metabolism ; Genomics/methods ; Glycoproteins/genetics ; Glycoproteins/metabolism ; Glycosylation ; Humans ; Neoplasm Invasiveness ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Phosphorylation ; Proteomics/methods ; Retinoblastoma Protein/genetics ; Retinoblastoma Protein/metabolism ; Signal Transduction/genetics ; Stromal Cells/metabolism ; Transcriptome/genetics | |||||
| Chemical Substances | Glycoproteins ; Retinoblastoma Protein ; CDK4 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 4 (EC 2.7.11.22) | |||||
| Language | English | |||||
| Publishing date | 2022-07-07 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 1432-1 | |||||
| ISSN | 1538-7445 ; 0008-5472 | |||||
| ISSN (online) | 1538-7445 | |||||
| ISSN | 0008-5472 | |||||
| DOI | 10.1158/0008-5472.CAN-21-1705 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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