TY  - JOUR
A1  - Marquardt, André
A1  - Hartrampf, Philipp
A1  - Kollmannsberger, Philip
A1  - Solimando, Antonio G.
A1  - Meierjohann, Svenja
A1  - Kübler, Hubert
A1  - Bargou, Ralf
A1  - Schilling, Bastian
A1  - Serfling, Sebastian E.
A1  - Buck, Andreas
A1  - Werner, Rudolf A.
A1  - Lapa, Constantin
A1  - Krebs, Markus
T1  - Predicting microenvironment in CXCR4- and FAP-positive solid tumors — a pan-cancer machine learning workflow for theranostic target structures
JF  - Cancers
N2  - (1) Background: C-X-C Motif Chemokine Receptor 4 (CXCR4) and Fibroblast Activation Protein Alpha (FAP) are promising theranostic targets. However, it is unclear whether CXCR4 and FAP positivity mark distinct microenvironments, especially in solid tumors. (2) Methods: Using Random Forest (RF) analysis, we searched for entity-independent mRNA and microRNA signatures related to CXCR4 and FAP overexpression in our pan-cancer cohort from The Cancer Genome Atlas (TCGA) database —  representing n = 9242 specimens from 29 tumor entities. CXCR4- and FAP-positive samples were assessed via StringDB cluster analysis, EnrichR, Metascape, and Gene Set Enrichment Analysis (GSEA). Findings were validated via correlation analyses in n = 1541 tumor samples. TIMER2.0 analyzed the association of CXCR4 / FAP expression and infiltration levels of immune-related cells. (3) Results: We identified entity-independent CXCR4 and FAP gene signatures representative for the majority of solid cancers. While CXCR4 positivity marked an immune-related microenvironment, FAP overexpression highlighted an angiogenesis-associated niche. TIMER2.0 analysis confirmed characteristic infiltration levels of CD8+ cells for CXCR4-positive tumors and endothelial cells for FAP-positive tumors. (4) Conclusions: CXCR4- and FAP-directed PET imaging could provide a non-invasive decision aid for entity-agnostic treatment of microenvironment in solid malignancies. Moreover, this machine learning workflow can easily be transferred towards other theranostic targets.
KW  - machine learning
KW  - tumor microenvironment
KW  - immune infiltration
KW  - angiogenesis
KW  - mRNA
KW  - miRNA
KW  - transcriptome
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-305036
SN  - 2072-6694
VL  - 15
IS  - 2
ER  - 
TY  - JOUR
A1  - Krebs, Markus
A1  - Solimando, Antonio Giovanni
A1  - Kalogirou, Charis
A1  - Marquardt, André
A1  - Frank, Torsten
A1  - Sokolakis, Ioannis
A1  - Hatzichristodoulou, Georgios
A1  - Kneitz, Susanne
A1  - Bargou, Ralf
A1  - Kübler, Hubert
A1  - Schilling, Bastian
A1  - Spahn, Martin
A1  - Kneitz, Burkhard
T1  - miR-221-3p Regulates VEGFR2 Expression in High-Risk Prostate Cancer and Represents an Escape Mechanism from Sunitinib In Vitro
JF  - Journal of Clinical Medicine
N2  - Downregulation of miR-221-3p expression in prostate cancer (PCa) predicted overall and cancer-specific survival of high-risk PCa patients. Apart from PCa, miR-221-3p expression levels predicted a response to tyrosine kinase inhibitors (TKI) in clear cell renal cell carcinoma (ccRCC) patients. Since this role of miR-221-3p was explained with a specific targeting of VEGFR2, we examined whether miR-221-3p regulated VEGFR2 in PCa. First, we confirmed VEGFR2/KDR as a target gene of miR-221-3p in PCa cells by applying Luciferase reporter assays and Western blotting experiments. Although VEGFR2 was mainly downregulated in the PCa cohort of the TCGA (The Cancer Genome Atlas) database, VEGFR2 was upregulated in our high-risk PCa cohort (n = 142) and predicted clinical progression. In vitro miR-221-3p acted as an escape mechanism from TKI in PC3 cells, as displayed by proliferation and apoptosis assays. Moreover, we confirmed that Sunitinib induced an interferon-related gene signature in PC3 cells by analyzing external microarray data and by demonstrating a significant upregulation of miR-221-3p/miR-222-3p after Sunitinib exposure. Our findings bear a clinical perspective for high-risk PCa patients with low miR-221-3p levels since this could predict a favorable TKI response. Apart from this therapeutic niche, we identified a partially oncogenic function of miR-221-3p as an escape mechanism from VEGFR2 inhibition.
KW  - microRNA-221
KW  - high-risk Prostate Cancer
KW  - angiogenesis
KW  - Sunitinib
KW  - Tyrosine kinase inhibition
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203168
SN  - 2077-0383
VL  - 9
IS  - 3
ER  -