Abstract
Microsatellite unstable (MSI) colorectal cancers (CRCs) are characterized by mutational inactivation of Transforming Growth Factor Beta Receptor Type 2 (TGFBR2). TGFBR2-deficient CRCs present altered target gene and protein expression. Such cellular alterations modulate the content of CRC-derived extracellular vesicles (EVs). EVs function as couriers of proteins, nucleic acids, and lipids in intercellular communication. At a qualitative level, we have previously shown that TGFBR2 deficiency causes overall alterations in the EV protein content. To deepen the basic understanding of altered protein dynamics, this work aimed to determine TGFBR2-dependent EV protein signatures in a quantitative manner. Using a stable isotope labeling with amino acids in cell culture (SILAC) approach for mass spectrometry-based quantification, 48 TGFBR2-regulated proteins were identified in MSI CRC-derived EVs. Overall, TGFBR2 deficiency caused upregulation of several EV proteins related to the extracellular matrix and nucleosome as well as downregulation of proteasome-associated proteins. The present study emphasizes the general overlap of proteins between EVs and their parental CRC cells but also highlights the impact of TGFBR2 deficiency on EV protein composition. From a clinical perspective, TGFBR2-regulated quantitative differences of protein expression in EVs might nominate novel biomarkers for liquid biopsy-based MSI typing in the future.
Highlights
Microsatellite unstable (MSI) colorectal cancers (CRCs) are caused by defects of the DNA mismatch repair system [1]
We have previously shown that TGFBR2 deficiency causes overall alterations in the extracellular vesicles (EVs) protein content
Using a stable isotope labeling with amino acids in cell culture (SILAC) approach for mass spectrometry-based quantification, 48 TGFBR2-regulated proteins were identified in MSI CRC-derived EVs
Summary
Microsatellite unstable (MSI) colorectal cancers (CRCs) are caused by defects of the DNA mismatch repair system [1]. About 90% of MSI colorectal tumors exhibit inactivating frameshift mutations in a polyadenine (A10) tract in exon 3 of Transforming Growth Factor Beta Receptor Type 2 (TGFBR2) gene [13,14]. TGFBR2 deficiency in colon epithelial cells is considered to drive MSI tumor progression by abrogating downstream Transforming Growth Factor-beta (TGF-β) signaling [13,15]. Missense mutations affecting TGFBR2 were identified in 15% of microsatellite stable colorectal tumors [16] and in several other tumor types, including breast [17], prostate [18] and renal cell carcinoma [19]. Downstream targets of TGFBR2-mediated signal transduction were identified at the transcriptomic and proteomic level of CRC cells and altered target gene and protein expression has been linked to TGFBR2 deficiency [21,22,23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
