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IGFBPs: Shaping CAF Heterogeneity in the Lung Tumor Microenvironment and Its Impact on Tumor Cells
CC BY 4.0 · Indian J Med Paediatr Oncol 2024; 45(S 01): S1-S16
DOI: DOI: 10.1055/s-0044-1788237
*Corresponding author: (e-mail: sarandkar@actrec.gov.in).
Abstract
Background: Cancer-associated fibroblasts (CAFs) are abundantly present in the tumor microenvironment of Non-Small Cell Lung Cancer (NSCLC). Insulin-like growth factor binding proteins (IGFBPs) are secretory proteins that regulate IGF signaling and are differentially expressed in CAFs compared to NFs. In this study, we investigated the role of IGFBP in CAFs.
Materials and Methods: IGFBP expression in CAF was validated by qRT-PCR, western blot and publicly available sc-RNA seq studies. Transient and stable IGFBP knockdowns were generated to understand IGFBP’s impact on CAF’s phenotype, and functional assays were performed. Transcriptome analyses were performed to understand how IGFBP rewires the CAF gene expression.
Results: We found that CAFs expressed higher levels of IGFBP5, 6, and 7 and were highly secreted compared to NFs. We also observed that tumor cells induce the expression of IGFBPs in fibroblasts in a contact-dependent manner. Additionally, CAF-secreted IGFBPs influence tumor cell migration, invasion, and proliferation and confer resistance against cisplatin. Interestingly, bulk RNA sequencing analysis revealed distinct gene signatures suggesting that even though IGFBP5, 6, and 7 are attributed to common CAF properties, each IGFBP has its independent mechanism of modulating CAF phenotype.
Conclusion: Our study highlighted that individual IGFBPs shape distinct CAF subpopulations and enhance tumor cell properties. Investigating and targeting the underlying mechanisms by which these different CAF subpopulations influence tumor cell properties and targeting them could support the available conventional therapies.
Publication History
Article published online:
08 July 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
*Corresponding author: (e-mail: sarandkar@actrec.gov.in).
Abstract
Background: Cancer-associated fibroblasts (CAFs) are abundantly present in the tumor microenvironment of Non-Small Cell Lung Cancer (NSCLC). Insulin-like growth factor binding proteins (IGFBPs) are secretory proteins that regulate IGF signaling and are differentially expressed in CAFs compared to NFs. In this study, we investigated the role of IGFBP in CAFs.
Materials and Methods: IGFBP expression in CAF was validated by qRT-PCR, western blot and publicly available sc-RNA seq studies. Transient and stable IGFBP knockdowns were generated to understand IGFBP’s impact on CAF’s phenotype, and functional assays were performed. Transcriptome analyses were performed to understand how IGFBP rewires the CAF gene expression.
Results: We found that CAFs expressed higher levels of IGFBP5, 6, and 7 and were highly secreted compared to NFs. We also observed that tumor cells induce the expression of IGFBPs in fibroblasts in a contact-dependent manner. Additionally, CAF-secreted IGFBPs influence tumor cell migration, invasion, and proliferation and confer resistance against cisplatin. Interestingly, bulk RNA sequencing analysis revealed distinct gene signatures suggesting that even though IGFBP5, 6, and 7 are attributed to common CAF properties, each IGFBP has its independent mechanism of modulating CAF phenotype.
Conclusion: Our study highlighted that individual IGFBPs shape distinct CAF subpopulations and enhance tumor cell properties. Investigating and targeting the underlying mechanisms by which these different CAF subpopulations influence tumor cell properties and targeting them could support the available conventional therapies.
No conflict of interest has been declared by the author(s).
Publication History
Article published online:
08 July 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India