MYC-ATF4-ASS1 axis governs intracellular arginine synthesis and dictates the immune microenvironment in melanoma
Mou, H.; Yakovishina, V.; Chen, Y.; Xiao, M.; Dunne, M.; Shi, N.; Thomas, M.; DeRosa, K.; Li, H.; Liu, Q.; Herlyn, M.
Show abstract
Drug resistance is a major challenge for both targeted therapies and immunotherapies in cancer. Arginine starvation has proven a promising strategy to overcome recurrent tumors. However, key molecules involved and how immune responses are elicited are not well understood. Here we identify in melanoma cells MYC-ATF4-ASS1 signaling as a pathway, which not only governs intracellular arginine synthesis but also modulates antitumor immunity. ATF4 knockout in melanoma cells phenocopied ASS1 knockout in the same cells, both showing greater sensitivity to arginine depletors such as ADI-PEG20. A combination strategy of BRAF/MEK inhibitors and an arginine depletor shows significant therapeutic effects in a immune-compromised mouse model. Both Atf4 and Ass1 knockout melanomas exhibited enhanced infiltration of Cd8+ T cells and significantly reduced tumor growth in a syngeneic mouse model. Single cell transcriptomics profiled the reshaped tumor microenvironment and revealed that a subset of resident macrophages were reprogrammed by endogenous arginine blockade. Overall, our findings reveal that the MYC-ATF4-ASS1 axis not only controls arginine vulnerability of melanomas but also shapes the immune microenvironment.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- BRAF inhibitors reprogram cancer-associated fibroblasts to drive matrix remodeling and therapeutic escape in melanoma 97%
- The lipid phosphatase activity of PTEN dampens FRA1 expression via AKT/mTOR signaling to suppress melanoma 96%
- A targetable PREX2/RAC1/PI3Kβ signalling axis confers resistance to clinically relevant therapeutic approaches in melanoma 96%
Similar papers in this journal
- PRMT7 ablation stimulates anti-tumor immunity and sensitizes melanoma to immune checkpoint blockade 96%
- Targeting KRAS-mutant stomach/colorectal tumours by disrupting the ERK2-p53 complex 95%
- Functional specialization of MITF, TFEB and TFE3 drives radically distinct adaptive gene expression programs in melanoma. 95%
Similar papers in this journal
- Tumor expressed CD95 causes suppression of anti-tumor activity of NK cells in a model of triple negative breast cancer 94%
- NDC80 status pinpoints mitotic kinase inhibitors as emerging therapeutic options in clear cell renal cell carcinoma 94%
- A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis 94%
"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.