TY  - JOUR
A1  - Sirtl, Simon
A1  - Knoll, Gertrud
A1  - Dieu Thuy, Trinh
A1  - Lang, Isabell
A1  - Siegmund, Daniela
A1  - Gross, Stefanie
A1  - Schuler-Thurner, Beatrice
A1  - Neubert, Patrick
A1  - Jantsch, Jonathan
A1  - Wajant, Harald
A1  - Ehrenschwender, Martin
T1  - Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors
JF  - Oncogene
N2  - Attempts to exploit the cytotoxic activity of death receptors (DR) for treating cancer have thus far been disappointing. DR activation in most malignant cells fails to trigger cell death and may even promote tumor growth by activating cell death-independent DR-associated signaling pathways. Overcoming apoptosis resistance is consequently a prerequisite for successful clinical exploitation of DR stimulation. Here we show that hyperosmotic stress in the tumor microenvironment unleashes the deadly potential of DRs by enforcing BCL-2 addiction of cancer cells. Hypertonicity robustly enhanced cytotoxicity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and other DR ligands in various cancer entities. Initial events in TRAIL DR signaling remained unaffected, but hypertonic conditions unlocked activation of the mitochondrial death pathway and thus amplified the apoptotic signal. Mechanistically, we demonstrate that hyperosmotic stress imposed a BCL-2-addiction on cancer cells to safeguard the integrity of the outer mitochondrial membrane (OMM), essentially exhausting the protective capacity of BCL-2-like pro-survival proteins. Deprivation of these mitochondrial safeguards licensed DR-generated truncated BH3-interacting domain death agonist (tBID) to activate BCL-2-associated X protein (BAX) and initiated mitochondrial outer membrane permeabilization (MOMP). Our work highlights that hyperosmotic stress in the tumor environment primes mitochondria for death and lowers the threshold for DR-induced apoptosis. Beyond TRAIL-based therapies, our findings could help to strengthen the efficacy of other apoptosis-inducing cancer treatment regimens.
KW  - apoptosis
KW  - cancer microenvironment
KW  - cytokines
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238327
VL  - 37
ER  - 
TY  - JOUR
A1  - Haake, Markus
A1  - Haack, Beatrice
A1  - Schäfer, Tina
A1  - Harter, Patrick N.
A1  - Mattavelli, Greta
A1  - Eiring, Patrick
A1  - Vashist, Neha
A1  - Wedekink, Florian
A1  - Genssler, Sabrina
A1  - Fischer, Birgitt
A1  - Dahlhoff, Julia
A1  - Mokhtari, Fatemeh
A1  - Kuzkina, Anastasia
A1  - Welters, Marij J. P.
A1  - Benz, Tamara M.
A1  - Sorger, Lena
A1  - Thiemann, Vincent
A1  - Almanzar, Giovanni
A1  - Selle, Martina
A1  - Thein, Klara
A1  - Späth, Jacob
A1  - Gonzalez, Maria Cecilia
A1  - Reitinger, Carmen
A1  - Ipsen-Escobedo, Andrea
A1  - Wistuba-Hamprecht, Kilian
A1  - Eichler, Kristin
A1  - Filipski, Katharina
A1  - Zeiner, Pia S.
A1  - Beschorner, Rudi
A1  - Goedemans, Renske
A1  - Gogolla, Falk Hagen
A1  - Hackl, Hubert
A1  - Rooswinkel, Rogier W.
A1  - Thiem, Alexander
A1  - Romer Roche, Paula
A1  - Joshi, Hemant
A1  - Pühringer, Dirk
A1  - Wöckel, Achim
A1  - Diessner, Joachim E.
A1  - Rüdiger, Manfred
A1  - Leo, Eugen
A1  - Cheng, Phil F.
A1  - Levesque, Mitchell P.
A1  - Goebeler, Matthias
A1  - Sauer, Markus
A1  - Nimmerjahn, Falk
A1  - Schuberth-Wagner, Christine
A1  - Felten, Stefanie von
A1  - Mittelbronn, Michel
A1  - Mehling, Matthias
A1  - Beilhack, Andreas
A1  - van der Burg, Sjoerd H.
A1  - Riedel, Angela
A1  - Weide, Benjamin
A1  - Dummer, Reinhard
A1  - Wischhusen, Jörg
T1  - Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment
JF  - Nature Communications
N2  - Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.
KW  - cancer microenvironment
KW  - immunotherapy
KW  - T cells
KW  - tumour immunology
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357333
VL  - 14
ER  - 
TY  - JOUR
A1  - Maichl, Daniela Simone
A1  - Kirner, Julius Arthur
A1  - Beck, Susanne
A1  - Cheng, Wen-Hui
A1  - Krug, Melanie
A1  - Kuric, Martin
A1  - Ade, Carsten Patrick
A1  - Bischler, Thorsten
A1  - Jakob, Franz
A1  - Hose, Dirk
A1  - Seckinger, Anja
A1  - Ebert, Regina
A1  - Jundt, Franziska
T1  - Identification of NOTCH-driven matrisome-associated genes as prognostic indicators of multiple myeloma patient survival
JF  - Blood Cancer Journal
N2  - No abstract available.
KW  - cancer microenvironment
KW  - myeloma
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357598
VL  - 13
ER  -