Spatial proteomics reveals mechanisms of cell-intrinsic tryptophan metabolism controlling ovarian cancer survival
Xu, T. T.; Metousis, A.; Kainacher, L.; Zhang, X.; Steigenberger, B.; Madden, K. G.; Schweitzer, L. C.; Duteil, C.; Rossini, S.; Lengyel, E.; Obermayr, E.; Shulman, Z.; Nordmann, T. M.; Lindberg, E. L.; Mann, M.; Murray, P. J.
Show abstract
Indole-2,3-dioxygenase (IDO1) depletes tryptophan to dampen anti-tumor T cells, yet IDO1 inhibitors (IDO1i) have failed clinically. Using deep visual proteomics, we isolated IDO1 high, medium and low ovarian tumor cells in situ and found IDO1 tightly linked to interferon-{gamma} (IFN-{gamma}) signaling and heterogeneously expressed. Across orthogonal models with tunable IDO1, IFN-{gamma} killed ovarian cancer via a pathway requiring IFN-{gamma} signaling, IDO1-dependent tryptophan depletion, and a biphasic integrated stress response that initially protects from starvation and later drives death. IDO1i or tryptophan supplementation rescued these effects, promoting tumor survival. These data reveal a context-dependent, tumor-suppressive facet of IDO1 and explain how IDO1i can paradoxically favor cancer viability. Our findings call for re-evaluation of IDO1 as a target and suggest exploiting the tryptophan-starvation/GCN2-ISR axis to enhance therapy.
Matching journals
The top 7 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- MLL1 regulates cytokine-driven cell migration and metastasis 95%
- Selective disruption of lipid peroxide homeostasis in intratumoral regulatory T cells by targeting FSP1 enhances cancer immunity 95%
- Mapping the genetic landscape of iron metabolism uncovers the SETD2 methyltransferase as a modulator of iron flux. 95%
Similar papers in this journal
- Neoplastic immune mimicry potentiates breast tumor progression 96%
- Targeting the dependence on PIK3C3-mTORC1 signaling in dormancy-prone breast cancer cells blunts metastasis initiation 96%
- Germline and somatic genetic variants in the p53 pathway interact to affect cancer risk, progression and drug response 95%
Similar papers in this journal
- An autophagy program that promotes T cell egress from the lymph node controls responses to immune checkpoint blockade 95%
- Mapping the tumor stress network reveals dynamic shifts in the stromal oxidative stress response 95%
- Stromal remodeling regulates dendritic cell abundance and activity in the tumor microenvironment 95%
Similar papers in this journal
- Mapping and modeling human colorectal carcinoma interactions with the tumor microenvironment 95%
- Rapidly induced drug adaptation mediates escape from BRAF inhibition in single melanoma cells 95%
- Rapid establishment of a tumor-retained state curtails the contribution of conventional NK cells to anti-tumor immunity in solid cancers 95%
Similar papers in this journal
- Sporadic activation of an oxidative stress-dependent NRF2-p53 signaling network in breast epithelial spheroids and premalignancies 96%
- MAPK and mTORC1 signaling converge on Cyclin D to enable cell-cycle re-entry in melanoma persister cells 95%
- Illuminating oncogenic KRAS signaling by multi-dimensional chemical proteomics 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.