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Multiomics Analysis of Spatially Distinct Stromal Cells Reveals Tumor-Induced O-Glycosylation of the CDK4-pRB Axis in Fibroblasts at the Invasive Tumor Edge.

Authors
  • Bouchard, Gina1, 2, 3
  • Garcia-Marques, Fernando Jose2
  • Karacosta, Loukia Georgiou1
  • Zhang, Weiruo1
  • Bermudez, Abel2
  • Riley, Nicholas McIlvain4
  • Varma, Sushama5
  • Mehl, Lindsey Catherine1
  • Benson, Jalen Anthony6
  • Shrager, Joseph B6
  • Bertozzi, Carolyn Ruth4
  • Pitteri, Sharon J2
  • Giaccia, Amato J3, 7
  • Plevritis, Sylvia Katina1, 2
  • 1 Department of Biomedical Data Science, Stanford University, Stanford, California.
  • 2 Department of Radiology, Canary Center for Cancer Early Detection, Palo Alto, California.
  • 3 Department of Radiation Oncology, Stanford University, Stanford, California.
  • 4 Departments of Chemistry, Stanford University, Stanford, California.
  • 5 Department of Pathology, Stanford University, Stanford, California.
  • 6 Department of Cardiothoracic Surgery, Stanford University, Stanford, California.
  • 7 Department of Oncology, University of Oxford, Oxford, United Kingdom. , (United Kingdom)
Type
Published Article
Journal
Cancer Research
Publisher
American Association for Cancer Research
Publication Date
Feb 15, 2022
Volume
82
Issue
4
Pages
648–664
Identifiers
DOI: 10.1158/0008-5472.CAN-21-1705
PMID: 34853070
Source
Medline
Language
English
License
Unknown

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. 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. ©2021 American Association for Cancer Research.

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