June 22nd, 2025
Recent Publications Harnessing the Power of Translatomics
Every week we provide a digest of a small number of recent interesting papers in the field of translatomics.
In this week’s Sunday papers,
- Yu et al. used ribosome profiling to reveal that the inclusion of an alternative exon in the 5’UTR of ALDOA mRNA enhanced the translation efficiency of the main protein coding ORF.
- Caggiano et al. used polysome profiling analysis to highlight the impact of splicing inhibition on the disrupted expression of DNA damage response (DDR) genes.
- Metge et al. applied polysome profiling to investigate increased ribosome biogenesis in tumour-associated macrophages and the impact on breast cancer progression.
Alternative splicing of ALDOA confers tamoxifen resistance in breast cancer
Oncogene, 2024
Yu, S., Wu, R., Si, Y., Fan, Z., Wang, Y., Yao, C., Sun, R., Xue, Y., Chen, Y., Wang, Z., Dong, S., Wang, N., Ling, X., Liang, Z., Bi, C., Yang, Y., Dong, W. and Sun, H.
The study identifies an alternative splicing event in the 5’ untranslated region (UTR) of the glycolytic enzyme ALDOA that impacts the synthesis of the ALDOA protein and promotes tamoxifen (TAM) resistance in estrogen receptor‑positive breast cancer. By analyzing nine pairs of primary and relapsed tumours from TAM-treated patients, ribosome profiling analysis discovered that exon 7.2 inclusion in the 5′ UTR of ALDOA strongly correlates with TAM resistance. This underscores how alternative splicing in the 5’UTR region (a.k.a. 5’ leader region) can modulate translation of the downstream main protein coding open reading frame. Functionally, this exon inclusion enhances translation of ALDOA mRNA, boosting ALDOA protein levels and subsequently activating mTOR signalling, which underlies increased cellular proliferation and TAM resistance in vitro.
The RNA-binding protein MSI1 directly facilitates the inclusion of ALDOA exon 7.2. High levels of MSI1 or exon 7.2 inclusion in tumours also predict poorer outcomes in endocrine therapy recipients. Importantly, pharmacological inhibition of ALDOA via Aldometanib re-sensitizes resistant breast cancer cells both in vitro and in vivo.
Overall, the findings revealed a clinically relevant 5’UTR splicing switch in ALDOA, regulated by MSI1, that drives TAM resistance and suggest ALDOA inhibition as a promising therapeutic strategy.
Learn more about EIRNA Bio’s ribosome profiling services here.
Transient splicing inhibition causes persistent DNA damage and chemotherapy vulnerability in triple-negative breast cancer
Cell Reports, 2024
Caggiano, C., Petrera, V., Ferri, M., Pieraccioli, M., Cesari, E., Di Leone, A., Sanchez, M.A., Fabi, A., Masetti, R., Naro, C. and Sette, C.
This study by Caggiano et al. investigates how transient inhibition of the U2 snRNP spliceosome complex impacts DNA repair mechanisms and chemotherapy sensitivity in triple-negative breast cancer (TNBC). A key feature of the paper is its use of polysome profiling to analyze the translational efficiency of DNA damage response (DDR) transcripts after splicing inhibition.. This splicing blockade selectively disrupts expression of DDR genes such as BRAC1 and BRAC2—likely due to their numerous small exons andcomplex exon-intron structures. Importantly, even a brief “pulse” of splicing inhibition dramatically enhances the cytotoxicity of DNA-damaging chemotherapy across multiple TNBC models by suppressing the expression of several DDR genes
These findings position U2 snRNP splicing as a critical regulator of DNA repair capacity and a novel therapeutic target in TNBC. By pre‑treating tumours with splicing inhibitors, it may be possible to sensitize cancers to conventional chemotherapy and PARP inhibitors, potentially overcoming resistance mechanisms. Thus, splicing modulation emerges as a promising adjunct strategy to enhance treatment efficacy in aggressive TNBC.
Learn more about EIRNA Bio’s polysome profiling service here.
Ribosomal RNA Biosynthesis Functionally Programs Tumor-Associated Macrophages to Support Breast Cancer Progression
Cancer Research, 2025
Metge, B.J., Williams, L.A., Swain, C.A., Hinshaw, D.C., Elhamamsy, A.R., Chen, D., Samant, R.S. and Shevde, L.A.
Macrophages are amongst the top immune cells that shape the microenvironment of developing mammary tumors. In this study, macrophages in early breast lesions and established tumours showed elevated ribosomal RNA (rRNA) biosynthesis signatures, a feature further amplified following radiotherapy or chemotherapy. Using polysome profiling analysis, tumour-associated macrophages (TAMs) exhibit increased rRNA synthesis, indicative of heightened ribosome biogenesis. Inhibiting rRNA transcription using RNA Pol I inhibitorBMH-21, reprograms TAMs from a pro-tumour to, a tumour-suppressive phenotype. This shift is mediated by nucleolar stress-induced activation of p53 and NF-κB signalling pathways, triggering a ribosome biogenesis checkpoint and inflammatory gene expression.
Importantly, targeting ribosome biogenesis in TAMs enhances the efficacy of neoadjuvant therapies in preclinical mammary cancer models. Thus, the authors identify rRNA biosynthesis as a critical tumor microenvironment dependency and propose that selective inhibition of RNA Pol I in macrophages represents a novel strategy for reprogramming the immune microenvironment and augmenting breast cancer treatment outcomes.
Learn more about EIRNA Bio’s polysome profiling service here.