TY - JOUR
T1 - Multiomics Analysis of Spatially Distinct Stromal Cells Reveals Tumor-Induced O-Glycosylation of the CDK4-pRB Axis in Fibroblasts at the Invasive Tumor Edge
AU - Bouchard, Gina
AU - Garcia-Marques, Fernando Jose
AU - Karacosta, Loukia Georgiou
AU - Zhang, Weiruo
AU - Bermudez, Abel
AU - Riley, Nicholas Mc Ilvain
AU - Varma, Sushama
AU - Mehl, Lindsey Catherine
AU - Benson, Jalen Anthony
AU - Shrager, Joseph B.
AU - Bertozzi, Carolyn Ruth
AU - Pitteri, Sharon J.
AU - Giaccia, Amato J.
AU - Plevritis, Sylvia Katina
N1 - Publisher Copyright:
© 2022 American Association for Cancer Research Inc.. All rights reserved.
PY - 2022/2/15
Y1 - 2022/2/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-21-1705
DO - 10.1158/0008-5472.CAN-21-1705
M3 - Article
C2 - 34853070
AN - SCOPUS:85124881553
SN - 0008-5472
VL - 82
SP - 648
EP - 664
JO - Cancer Research
JF - Cancer Research
IS - 4
ER -