The rapidly evolving field of cancer research has seen significant advances in understanding the complex mechanisms underpinning tumour development, progression, and resistance to therapy. Recent studies leveraging translatomics have provided profound insights into the role of mRNA translation and its regulation in cancer, offering new avenues for therapeutic intervention and diagnostic approaches. This blog post summarises the findings from several pivotal studies – all of which were showcased in our 2023 collection of The Sunday Papers, highlighting the impact of translatomics in unveiling novel cancer mechanisms and potential targets for treatment.
Decoding Cryptic Proteins in Cancer Through CRISPR/Cas9
Zheng et al. (2023), utilised CRISPR/Cas9 alongside ribosome profiling to uncover cryptic proteins encoded by long non-coding RNAs (lncRNAs) in breast cancer. Their work identifies a protein, GT3-INCP, derived from the LINC00992 lncRNA, which interacts with GATA3, suggesting a novel pathway involved in breast cancer pathogenesis. This study not only challenges the traditional view of lncRNAs but also opens a new frontier for therapeutic targets in cancer treatment.
The Double-Edged Sword of IDO1 Inhibition
Kenski et al. (2023) reveal the adverse effects of inhibiting IDO1, a strategy initially thought to enhance immunotherapy efficacy in melanoma. Their research demonstrates that IDO1 inhibition inadvertently promotes tumour protection by modulating translational responses to immune-induced stress, thereby enhancing the survival pathways of cancer cells. This counterintuitive finding emphasizes the complexity of cancer biology and the need for a nuanced approach to immunotherapy.
Targeting RRP15 in Colorectal Cancer
Dong et al. (2023), highlight the role of RRP15 in colorectal cancer (CRC) proliferation and metastasis. By inducing ribosome stress and upregulating LZTS2 translation, RRP15 deficiency suppresses the Wnt/β-catenin signalling pathway, presenting a novel target for CRC therapy. This study underscores the importance of ribosomal proteins and their biogenesis in cancer progression.
CDK13 and Tumourigenic Protein Synthesis
A study by Wu et al. (2023) uncovers the role of CDK13 in phosphorylating elements of the translation machinery, thus promoting the synthesis of proteins that drive tumourigenesis in colorectal cancer. By directly impacting the translation initiation factors, CDK13 emerges as a critical player in cancer biology, offering a potential target for therapeutic intervention.
m6A Modification and Angiogenesis in Lung Cancer
Zhang et al. (2023) research delves into the role of m6A modification in regulating VEGFA translation, a key factor in angiogenesis and tumour growth in lung cancer. Their findings suggest that targeting the m6A modification pathway could offer a new strategy for inhibiting tumour angiogenesis, a critical component of cancer progression.
Overcoming Drug Resistance in Breast Cancer
Meng et al. (2023) introduce a bi-steric mTORC1-selective inhibitor, RMC-6272, as a promising approach to overcome drug resistance in breast cancer. By selectively targeting mTORC1, this compound offers a new avenue for treating cancers that have become resistant to current therapies, highlighting the potential of targeted molecular inhibition in cancer treatment.
The Metabolic Regulation of Gastric Cancer
Yang et al. (2023) explore the role of N4‐acetylcytidine (ac4C) modification in driving glycolysis addiction in gastric cancer. Their findings reveal a feedback loop involving NAT10, SEPT9, and HIF‐1α, emphasizing the complexity of metabolic regulation in cancer and the potential for targeting these pathways in therapy.
Unravelling the Immunopeptidome
Ruiz Cuevas et al. (2023), through their development of BamQuery, offer a tool for exploring the immunopeptidome and identifying actionable tumour antigens. This advancement highlights the potential for personalized cancer immunotherapy by targeting specific tumour antigens derived from non-canonical genomic regions.
Concluding Thoughts
The studies discussed here illustrate the power of translatomics in advancing our understanding of cancer biology. By shedding light on the intricate mechanisms of mRNA translation and its regulation, these findings pave the way for the development of novel diagnostic tools and therapeutic strategies. The ability to decode the complex language of cancer cells at the translational level represents a significant leap forward in our quest to conquer cancer, offering hope for more effective and personalized treatments in the future.
For more detailed summaries of each of the above papers, visit our Sunday Papers collection here: https://eirnabio.com/category/sunday-papers/ . New papers published every Sunday!
References
Zheng, C., Wei, Y., Zhang, P., Xu, L., Zhang, Z., Lin, K., Hou, J., Lv, X., Ding, Y., Chiu, Y., & Jain, A. (2023). CRISPR/Cas9 screen uncovers functional translation of cryptic lncRNA-encoded open reading frames in human cancer. Journal of Clinical Investigation.
Kenski, J.C., Huang, X., Vredevoogd, D.W., de Bruijn, B., Traets, J.J., Ibáñez-Molero, S., Schieven, S.M., van Vliet, A., Krijgsman, O., Kuilman, T., & Pozniak, J. (2023). An adverse tumour-protective effect of IDO1 inhibition. Cell Reports Medicine.
Dong, Z., Li, J., Dai, W., Yu, D., Zhao, Y., Liu, S., Li, X., Zhang, Z., Zhang, R., Liang, X., & Kong, Q. et al. (2023). RRP15 deficiency induces ribosome stress to inhibit colorectal cancer proliferation and metastasis via LZTS2-mediated β-catenin suppression. Cell Death & Disease.
Wu, C., Xie, T., Guo, Y., Wang, D., Qiu, M., Han, R., Qing, G., Liang, K., & Liu, H. et al. (2023). CDK13 phosphorylates the translation machinery and promotes tumourigenic protein synthesis. Oncogene.
Zhang, H., Zhou, J., Li, J., Wang, Z., Chen, Z., Lv, Z., Ge, L., Xie, G., Deng, G., Rui, Y., & Wang, H. (2023). N6-methyladenosine promotes translation of VEGFA to accelerate angiogenesis in lung cancer. Cancer Research.
Meng, D., Zhao, X., Yang, Y.C., Navickas, A., Helland, C., Goodarzi, H., Singh, M., & Bandyopadhyay, S. (2023). A bi-steric mTORC1-selective inhibitor overcomes drug resistance in breast cancer. Oncogene.
Yang, Q., Lei, X., He, J., Peng, Y., Zhang, Y., Ling, R., Wu, C., Zhang, G., Zheng, B., Chen, X., & Zou, B. (2023). N4‐Acetylcytidine Drives Glycolysis Addiction in Gastric Cancer via NAT10/SEPT9/HIF‐1α Positive Feedback Loop. Advanced Science.
Ruiz Cuevas, M. V., Hardy, M.-P., Larouche, J.-D., Apavaloaei, A., Kina, E., Vincent, K., Gendron, P., Laverdure, J.-P., Durette, C., Thibault, P., Lemieux, S., Perreault, C., & Ehx, G. (2023). BamQuery: a proteogenomic tool to explore the immunopeptidome and prioritize actionable tumour antigens. Genome Biology.