TY  - JOUR
A1  - Kreß, Julia Katharina Charlotte
A1  - Jessen, Christina
A1  - Hufnagel, Anita
A1  - Schmitz, Werner
A1  - Da Xavier Silva, Thamara Nishida
A1  - Ferreira Dos Santos, Ancély
A1  - Mosteo, Laura
A1  - Goding, Colin R.
A1  - Friedmann Angeli, José Pedro
A1  - Meierjohann, Svenja
T1  - The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2
JF  - Cell Reports
N2  - Highlights
• The integrated stress response leads to a general ATF4-dependent activation of NRF2
• ATF4 causes a CHAC1-dependent GSH depletion, resulting in NRF2 stabilization
• An elevation of NRF2 transcript levels fosters this effect
• NRF2 supports the ISR/ATF4 pathway by improving cystine and antioxidant supply

Summary
The redox regulator NRF2 becomes activated upon oxidative and electrophilic stress and orchestrates a response program associated with redox regulation, metabolism, tumor therapy resistance, and immune suppression. Here, we describe an unrecognized link between the integrated stress response (ISR) and NRF2 mediated by the ISR effector ATF4. The ISR is commonly activated after starvation or ER stress and plays a central role in tissue homeostasis and cancer plasticity. ATF4 increases NRF2 transcription and induces the glutathione-degrading enzyme CHAC1, which we now show to be critically important for maintaining NRF2 activation. In-depth analyses reveal that NRF2 supports ATF4-induced cells by increasing cystine uptake via the glutamate-cystine antiporter xCT. In addition, NRF2 upregulates genes mediating thioredoxin usage and regeneration, thus balancing the glutathione decrease. In conclusion, we demonstrate that the NRF2 response serves as second layer of the ISR, an observation highly relevant for the understanding of cellular resilience in health and disease.
KW  - NRF2
KW  - ATF4
KW  - integrated stress response
KW  - CHAC1
KW  - melanoma
KW  - SLC7A11
KW  - GSH
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350312
VL  - 42
IS  - 7
ER  - 
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  -