bims-ectoca 2024-09-22 papers

Issue of 2024‒09‒22
six papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Oncogene. 2024 Sep 17.

The RNA helicase DDX21 activates YAP to promote tumorigenesis and is transcriptionally upregulated by β-catenin in colorectal cancer.

Wenbo Tang, Yiqing Yang, Zhuoyue Fu, Weimin Xu, Weijun Ou, Fangyuan Liu, Peng Du, Chen-Ying Liu.

The RNA helicase DDX21 is vital for ribosome biogenesis and is upregulated in CRC, but the mechanism by which DDX21 is dysregulated and by which DDX21 promotes tumorigenesis in CRC remains poorly understood. Here, we showed that DDX21 is a direct transcriptional target gene of β-catenin and mediates the protumorigenic function of β-catenin in CRC. DDX21 expression is correlated with the expression and activity of β-catenin, and high DDX21 expression is associated with a poor prognosis in CRC patients. Loss of DDX21 leads to cytoplasmic translocation and decreased transcriptional activity of YAP and suppresses the proliferation and migration of CRC cells, which can be partially rescued by YAP reactivation. Importantly, by using translation elongation inhibitors and DNA intercalators, we showed that ribosomal stress upregulates DDX21 expression and induces the downregulation of LATS and the activation of YAP, probably through the ZAKα-MKK4/7-JNK axis. Overall, our study revealed the transcriptional activation mechanism of DDX21 in CRC and the activation of YAP in the ribosomal stress response, indicating the potential of combination therapy involving the induction of ribosomal stress and YAP inhibition.

DOI: https://doi.org/10.1038/s41388-024-03160-8

Front Oncol. 2024 ;14 1328728

Mechanisms of resistance to KRASG12C inhibitors in KRASG12C-mutated non-small cell lung cancer.

Ali Chour, Anne-Claire Toffart, Elodie Berton, Michael Duruisseaux.

The KRAS protein, a product of the KRAS gene (V-ki-ras2 Kirsten rat sarcoma viral oncogene homolog), functions as a small GTPase that alternates between an active GTP-bound state (KRAS(ON)) and an inactive GDP-bound state (KRAS(OFF)). The KRASG12C mutation results in the accumulation of KRASG12C(OFF), promoting cell cycle survival and proliferation primarily through the canonical MAPK and PI3K pathways. The KRASG12C mutation is found in 13% of lung adenocarcinomas. Previously considered undruggable, sotorasib and adagrasib are the first available OFF-state KRASG12C inhibitors, but treatment resistance is frequent. In this review, after briefly summarizing the KRAS pathway and the mechanism of action of OFF-state KRASG12C inhibitors, we discuss primary and acquired resistance mechanisms. Acquired resistance is the most frequent, with "on-target" mechanisms such as a new KRAS mutation preventing inhibitor binding; and "off-target" mechanisms leading to bypass of KRAS through gain-of-function mutations in other oncogenes such as NRAS, BRAF, and RET; or loss-of-function mutations in tumor suppressor genes such as PTEN. Other "off-target" mechanisms described include epithelial-to-mesenchymal transition and histological transformation. Multiple co-existing mechanisms can be found in patients, but few cases have been published. We highlight the lack of data on non-genomic resistance and the need for comprehensive clinical studies exploring histological, genomic, and non-genomic changes at resistance. This knowledge could help foster new treatment initiatives in this challenging context.

Keywords: KRASG12C inhibitor resistance; KRASG12C mutation; adagrasib; non-small cell lung cancer; sotorasib; translational research

DOI: https://doi.org/10.3389/fonc.2024.1328728

bioRxiv. 2024 Sep 06. pii: 2024.09.05.611456. [Epub ahead of print]

Image-Based Quantitative Single-Cell Method Showed Increase of Global Chromatin Accessibility in Tumor Compared to Normal Cells.

Mairead Commane, Vidula Jadhav, Katerina Leonova, Brian Buckley, Henry Withers, Katerina Gurova.

The phenotypic plasticity of cancer cells has recently emerged as an important factor of treatment failure. The mechanisms of phenotypic plasticity are not fully understood. One of the hypotheses is that the degree of chromatin accessibility defines the easiness of cell transitions between different phenotypes. To test this, a method to compare overall chromatin accessibility between cells in a population or between cell populations is needed. We propose to measure chromatin accessibility by fluorescence signal from nuclei of cells stained with DNA binding fluorescent molecules. This method is based on the observations that small molecules bind nucleosome-free DNA more easily than nucleosomal DNA. Thus, nuclear fluorescence is proportional to the amount of nucleosome-free DNA, serving as a measure of chromatin accessibility. We optimized the method using several DNA intercalators and minor groove binders and known chromatin-modulating agents and demonstrated that chromatin accessibility is increased upon oncogene-induced transformation and further in tumor cells.

DOI: https://doi.org/10.1101/2024.09.05.611456

J Gastrointest Oncol. 2024 Aug 31. 15(4): 1712-1722

YAP-based nomogram predicts poor prognosis in patients with hepatocellular carcinoma after curative surgery.

Wenxuan Zhou, Feiyang Ye, Gaowei Yang, Chenghu Liu, Zeya Pan, Chengjing Zhang, Hui Liu.

Background: Hepatocellular carcinoma (HCC) ranks prominently in cancer-related mortality globally. Surgery remains the main therapeutic option for the treatment of HCC, but high post-operative recurrence rate makes prognostic prediction challenging. The quest for a reliable model to predict HCC recurrence continues to enhance prognosis. We aim to develop a nomogram with multiple factors to accurately estimate the risk of post-operative recurrence in patients with HCC.Methods: A single-center retrospective study on 262 patients who underwent partial hepatectomy for HCC at the Eastern Hepatobiliary Surgery Hospital from May 2010 to April 2013 was conducted where immunohistochemistry assessed Yes-associated protein (YAP) expression in HCC. In the training cohort, a nomogram that incorporated YAP expression and clinicopathological features was constructed to predict 2-, 3-, and 5-year recurrence-free survival (RFS). The performance of the nomogram was assessed with respect to discrimination calibration, and clinical usefulness with external validation.
Results: A total of 262 patients who underwent partial hepatectomy for HCC at the Eastern Hepatobiliary Surgery Hospital were included in our study. HCC patients with high YAP expression exhibited significantly higher recurrence and reduced overall survival (OS) rates compared to those with low YAP expression (P<0.001). YAP was significantly associated with alpha-fetoprotein (AFP) (P=0.03), microvascular invasion (MVI) (P<0.001), and tumor differentiation grade (P<0.001). In the training cohort, factors like YAP expression, hepatitis B surface antigen (HBsAg), hepatitis B virus deoxyribonucleic acid (HBV-DNA), Child-Pugh stage, tumor size, MVI, and tumor differentiation were identified as key elements for the predictive model. Two YAP-centric Nomograms were developed, with one focused on predicting postoperative OS and the other on RFS. The calibration curve further confirmed the model's accuracy in the training cohort. The validation cohort confirmed the model's predictive accuracy.
Conclusions: The proposed nomogram combining the YAP, a predictor of HCC progression, and clinical features achieved more-accurate prognostic prediction for patients with HCC after partial hepatectomy, which may help clinicians implement more appropriate interventions.

Keywords: Hepatocellular carcinoma (HCC); Yes-associated protein (YAP); nomogram; prognosis

DOI: https://doi.org/10.21037/jgo-24-36

Life Sci Alliance. 2024 Dec;pii: e202402849. [Epub ahead of print]7(12):

Nanoscale imaging of DNA-RNA identifies transcriptional plasticity at heterochromatin.

Christelle Guillermier, Naveen Vg Kumar, Ronan C Bracken, Diana Alvarez, John O'Keefe, Aditi Gurkar, Jonathan D Brown, Matthew L Steinhauser.

The three-dimensional structure of DNA is a biophysical determinant of transcription. The density of chromatin condensation is one determinant of transcriptional output. Chromatin condensation is generally viewed as enforcing transcriptional suppression, and therefore, transcriptional output should be inversely proportional to DNA compaction. We coupled stable isotope tracers with multi-isotope imaging mass spectrometry to quantify and image nanovolumetric relationships between DNA density and newly made RNA within individual nuclei. Proliferative cell lines and cycling cells in the murine small intestine unexpectedly demonstrated no consistent relationship between DNA density and newly made RNA, even though localized examples of this phenomenon were detected at nuclear-cytoplasmic transitions. In contrast, non-dividing hepatocytes demonstrated global reduction in newly made RNA and an inverse relationship between DNA density and transcription, driven by DNA condensates at the nuclear periphery devoid of newly made RNA. Collectively, these data support an evolving model of transcriptional plasticity that extends at least to a subset of chromatin at the extreme of condensation as expected of heterochromatin.

DOI: https://doi.org/10.26508/lsa.202402849

Hum Mol Genet. 2024 Sep 15. pii: ddae138. [Epub ahead of print]

Deciphering single-cell gene expression variability and its role in drug response.

Sizhe Liu, Liang Chen.

The effectiveness of drug treatments is profoundly influenced by individual responses, which are shaped by gene expression variability, particularly within pharmacogenes. Leveraging single-cell RNA sequencing (scRNA-seq) data, our study explores the extent of expression variability among pharmacogenes in a wide array of cell types across eight different human tissues, shedding light on their impact on drug responses. Our findings broaden the established link between variability in pharmacogene expression and drug efficacy to encompass variability at the cellular level. Moreover, we unveil a promising approach to enhance drug efficacy prediction. This is achieved by leveraging a combination of cross-cell and cross-individual pharmacogene expression variation measurements. Our study opens avenues for more precise forecasting of drug performance, facilitating tailored and more effective treatments in the future.

Keywords: drug efficacy; expression variation; machine learning; pharmacogene; single-cell RNA-seq

DOI: https://doi.org/10.1093/hmg/ddae138