Hanahan, D. Hallmarks of cancer: new dimensions. Cancer Discov. 12, 31–46 (2022).
Google Scholar
Martínez-Reyes, I. & Chandel, N. S. Cancer metabolism: looking forward. Nat. Rev. Cancer 21, 669–680 (2021).
Google Scholar
Zhang, L. et al. Targets of tumor microenvironment for potential drug development. MedComm Oncol. 3, e68 (2024).
Google Scholar
Pavlova, N. N., Zhu, J. & Thompson, C. B. The hallmarks of cancer metabolism: Still emerging. Cell Metab. 34, 355–377 (2022).
Google Scholar
Vander Heiden, M. G. & DeBerardinis, R. J. Understanding the intersections between metabolism and cancer biology. Cell 168, 657–669 (2017).
Google Scholar
Eagle, H. Nutrition needs of mammalian cells in tissue culture. Science 122, 501–514 (1955).
Google Scholar
Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040–1044 (2012).
Google Scholar
Hosios, A. M. et al. Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells. Dev. Cell 36, 540–549 (2016).
Google Scholar
Birsoy, K. et al. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides. Nature 508, 108–112 (2014).
Google Scholar
Yuneva, M. O. et al. The metabolic profile of tumors depends on both the responsible genetic lesion and tissue type. Cell Metab. 15, 157–170 (2012).
Google Scholar
Pavlova, N. N. et al. As extracellular glutamine levels decline, asparagine becomes an essential amino acid. Cell Metab. 27, 428–438 (2018).
Google Scholar
Krall, A. S. et al. Asparagine couples mitochondrial respiration to ATF4 activity and tumor growth. Cell Metab. 33, 1013–1026 (2021).
Google Scholar
Zhao, T., Du, J. & Zeng, H. Interplay between endoplasmic reticulum stress and non-coding RNAs in cancer. J. Hematol. Oncol. 13, 163 (2020).
Google Scholar
Zhao, Y. et al. ROS signaling under metabolic stress: cross-talk between AMPK and AKT pathway. Mol. Cancer 16, 79 (2017).
Google Scholar
Zielke, S. et al. ATF4 links ER stress with reticulophagy in glioblastoma cells. Autophagy 17, 2432–2448 (2021).
Google Scholar
Balsa, E. et al. ER and nutrient stress promote assembly of respiratory chain supercomplexes through the PERK–eIF2α axis. Mol. Cell 74, 877–890 (2019).
Google Scholar
Gwinn, D. M. et al. Oncogenic KRAS regulates amino acid homeostasis and asparagine biosynthesis via ATF4 and alters sensitivity to L-asparaginase. Cancer Cell 33, 91–107 (2018).
Google Scholar
Magne, L. et al. ATF4 and the integrated stress response are induced by ethanol and cytochrome P450 2E1 in human hepatocytes. J. Hepatol. 54, 729–737 (2011).
Google Scholar
Williams, R. T. et al. ZBTB1 regulates asparagine synthesis and leukemia cell response to L-asparaginase. Cell Metab. 31, 852–861 (2020).
Google Scholar
Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011).
Google Scholar
Zhou, Z. et al. Mechanism of RNA modification N6-methyladenosine in human cancer. Mol. Cancer 19, 104 (2020).
Google Scholar
Huang, H., Weng, H. & Chen, J. m6A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell 37, 270–288 (2020).
Google Scholar
Tao, L. et al. Epigenetic regulation in cancer therapy: from mechanisms to clinical advances. MedComm Oncol. 3, e59 (2024).
Google Scholar
Chen, X. Y., Zhang, J. & Zhu, J. S. The role of m6A RNA methylation in human cancer. Mol. Cancer 18, 103 (2019).
Google Scholar
Liu, H. et al. ALKBH5-mediated m6A demethylation of GLUT4 mRNA promotes glycolysis and resistance to HER2-targeted therapy in breast cancer. Cancer Res. 82, 3974–3986 (2022).
Google Scholar
Yu, H. et al. ALKBH5 inhibited cell proliferation and sensitized bladder cancer cells to cisplatin by m6A–CK2α-mediated glycolysis. Mol. Ther. Nucleic Acids 23, 27–41 (2021).
Google Scholar
Ahola, S. et al. OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy. Cell Metab. 34, 1875–1891 (2022).
Google Scholar
Guo, X. et al. Mitochondrial stress is relayed to the cytosol by an OMA1–DELE1–HRI pathway. Nature 579, 427–432 (2020).
Google Scholar
Nakamura, A. et al. Inhibition of GCN2 sensitizes ASNS-low cancer cells to asparaginase by disrupting the amino acid response. Proc. Natl Acad. Sci. USA 115, E7776–E7785 (2018).
Google Scholar
Sidrauski, C. et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife 2, e00498 (2013).
Google Scholar
Smola, M. J., Rice, G. M., Busan, S., Siegfried, N. A. & Weeks, K. M. Selective 2′-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) for direct, versatile and accurate RNA structure analysis. Nat. Protoc. 10, 1643–1669 (2015).
Google Scholar
Siegfried, N. A., Busan, S., Rice, G. M., Nelson, J. A. & Weeks, K. M. RNA motif discovery by SHAPE and mutational profiling (SHAPE-MaP). Nat. Methods 11, 959–965 (2014).
Google Scholar
Xia, Z. et al. Epitranscriptomic editing of the RNA N6-methyladenosine modification by dCasRx conjugated methyltransferase and demethylase. Nucleic Acids Res. 49, 7361–7374 (2021).
Google Scholar
Nogueira, V. & Hay, N. Molecular pathways: reactive oxygen species homeostasis in cancer cells and implications for cancer therapy. Clin. Cancer Res. 19, 4309–4314 (2013).
Google Scholar
Reid, M. A. et al. The B55α subunit of PP2A drives a p53-dependent metabolic adaptation to glutamine deprivation. Mol. Cell 50, 200–211 (2013).
Google Scholar
Hast, B. E. et al. Cancer-derived mutations in KEAP1 impair NRF2 degradation but not ubiquitination. Cancer Res. 74, 808–817 (2014).
Google Scholar
Berger, A. H. et al. High-throughput phenotyping of lung cancer somatic mutations. Cancer Cell 30, 214–228 (2016).
Google Scholar
Jaramillo, M. C. & Zhang, D. D. The emerging role of the Nrf2–Keap1 signaling pathway in cancer. Genes Dev. 27, 2179–2191 (2013).
Google Scholar
Romero, R. et al. Keap1 mutation renders lung adenocarcinomas dependent on Slc33a1. Nat. Cancer 1, 589–602 (2020).
Google Scholar
Roundtree, I. A. et al. YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs. eLife 6, e31311 (2017).
Komatsu, T. E. et al. Regulatory analysis of effects of hepatitis C virus NS5A polymorphisms on efficacy of elbasvir and grazoprevir. Gastroenterology 152, 586–597 (2017).
Google Scholar
Xiao, Z., Dai, Z. & Locasale, J. W. Metabolic landscape of the tumor microenvironment at single cell resolution. Nat. Commun. 10, 3763 (2019).
Google Scholar
Lyssiotis, C. A. & Kimmelman, A. C. Metabolic interactions in the tumor microenvironment. Trends Cell Biol. 27, 863–875 (2017).
Google Scholar
Elia, I. & Haigis, M. C. Metabolites and the tumour microenvironment: from cellular mechanisms to systemic metabolism. Nat. Metab. 3, 21–32 (2021).
Google Scholar
Lin, S. C. & Hardie, D. G. AMPK: sensing glucose as well as cellular energy status. Cell Metab. 27, 299–313 (2018).
Google Scholar
González, A., Hall, M. N., Lin, S. C. & Hardie, D. G. AMPK and TOR: the yin and yang of cellular nutrient sensing and growth control. Cell Metab. 31, 472–492 (2020).
Google Scholar
Abu-Remaileh, M. et al. Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science 358, 807–813 (2017).
Google Scholar
Knott, S. R. V. et al. Asparagine bioavailability governs metastasis in a model of breast cancer. Nature 554, 378–381 (2018).
Google Scholar
Hinze, L. et al. Exploiting the therapeutic interaction of WNT pathway activation and asparaginase for colorectal cancer therapy. Cancer Discov. 10, 1690–1705 (2020).
Google Scholar
Wu, J. et al. Asparagine enhances LCK signalling to potentiate CD8+ T-cell activation and anti-tumour responses. Nat. Cell Biol. 23, 75–86 (2021).
Google Scholar
Xiao, S. et al. The RNA N6-methyladenosine modification landscape of human fetal tissues. Nat. Cell Biol. 21, 651–661 (2019).
Google Scholar
Zheng, G. et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol. Cell 49, 18–29 (2013).
Google Scholar
Chang, G. et al. YTHDF3 induces the translation of m6A-enriched gene transcripts to promote breast cancer brain metastasis. Cancer Cell 38, 857–871 (2020).
Google Scholar
Su, R. et al. R-2HG exhibits anti-tumor activity by targeting FTO/m6A/MYC/CEBPA signaling. Cell 172, 90–105 (2018).
Google Scholar
He, L. et al. Functions of N6-methyladenosine and its role in cancer. Mol. Cancer 18, 176 (2019).
Google Scholar
Deng, L. J. et al. m6A modification: recent advances, anticancer targeted drug discovery and beyond. Mol. Cancer 21, 52 (2022).
Google Scholar
Zhou, J. et al. N6-methyladenosine guides mRNA alternative translation during integrated stress response. Mol. Cell 69, 636–647 (2018).
Google Scholar
Liu, X. et al. ATOH8 binds SMAD3 to induce cellular senescence and prevent Ras-driven malignant transformation. Proc. Natl Acad. Sci. USA 120, e2208927120 (2023).
Google Scholar
Yang, X. et al. m6A-dependent modulation via IGF2BP3/MCM5/Notch axis promotes partial EMT and LUAD metastasis. Adv Sci. 10, e2206744 (2023).
Google Scholar
Tian, H. et al. AKT-induced lncRNA VAL promotes EMT-independent metastasis through diminishing Trim16-dependent Vimentin degradation. Nat. Commun. 11, 5127 (2020).
Google Scholar
Wu, S. et al. Long non-coding RNA LEISA promotes progression of lung adenocarcinoma via enhancing interaction between STAT3 and IL-6 promoter. Oncogene 40, 3449–3459 (2021).
Google Scholar
Busan, S. & Weeks, K. M. Accurate detection of chemical modifications in RNA by mutational profiling (MaP) with ShapeMapper 2. RNA 24, 143–148 (2018).
Google Scholar
Pan, X., Fang, Y., Li, X., Yang, Y. & Shen, H. B. RBPsuite: RNA-protein binding sites prediction suite based on deep learning. BMC Genomics 21, 884 (2020).
Google Scholar
Cook, K. B., Kazan, H., Zuberi, K., Morris, Q. & Hughes, T. R. RBPDB: a database of RNA-binding specificities. Nucleic Acids Res. 39, D301–D308 (2011).
Google Scholar
Agostini, F. et al. catRAPID omics: a web server for large-scale prediction of protein–RNA interactions. Bioinformatics 29, 2928–2930 (2013).
Google Scholar
Wang, S. et al. The N6-methyladenosine epitranscriptomic landscape of lung adenocarcinoma. Cancer Discov. 14, 2279–2299 (2024).
Google Scholar
Momcilovic, M. et al. The GSK3 signaling axis regulates adaptive glutamine metabolism in lung squamous cell carcinoma. Cancer Cell 33, 905–921 (2018).
Google Scholar
Wei, X. et al. METTL3 preferentially enhances non-m6A translation of epigenetic factors and promotes tumourigenesis. Nat. Cell Biol. 24, 1278–1290 (2022).
Google Scholar

