Biology subjects

Balmain, A.

Publications and source records attributed to Balmain, A..

5 recordsLinked to original sources

bioRxiv2024

The interplay between dormant mutated cells and tumor promotion by chronic tissue damage in determining cancer risk.

While the causal role of mutagenic carcinogens in tumor development is well established, the relative contribution of environmental tumor promoting factors, wounding, and chronic inflammation is still unclear. Recent sequencing studies have suggested that most environmental carcinogens act as promoters rather than through mechanisms that involve direct induction of point mutations, but whether cancer risk factors such as obesity, chronic inflammation, wounding, or tumor promoters contribute directly or indirectly to mutation burden, or induce novel signatures, has not been investigated. Here, we present WGS analysis of over 100 mouse skin tumors to compare the effects of exposure to mutagens, the tumor promoter TPA, chronic wounding, obesity, or chemotherapy, on mutational burden and cancer risk. All tumors initiated by the carcinogen Dimethylbenzanthracene (DMBA) show a very strong A>T mutational signature (SBS.DMBA) attributable to a single exposure to this carcinogen. The number of SBS.DMBA mutations also showed a strong correlation with the "clock" signature SBS5, suggesting that one treatment with this mutagen can induce mutational signatures attributed to endogenous processes. No specific signatures could be attributed to obesity, high fat diet, wounding, or TPA. Cells carrying thousands of mutations persist over very long periods without inducing tumors or causing pathological changes but can give rise to tumors after short term exposure to TPA. Furthermore, normal cell turnover and proliferation during fetal and adult growth, is not sufficient for promotion, but tissue damage followed by regenerative proliferation seems to be required for tumor development. We conclude that tumor promoters, chronic inflammation, wounding, and obesity do not contribute significantly to tumor mutational burden, and that the rate-limiting determinant of tumor growth is exposure to a tumor promoter rather than the nature or number of genomic point mutations. These data are highly relevant to the recent demonstration of persistent oncogenic mutations in histologically normal human tissues during ageing.

cancer biology↗

bioRxiv2023

Gene networks reveal stem-cell state convergence during preneoplasia and progression to malignancy in multistage skin carcinogenesis

Adult mammalian stem cells play critical roles in normal tissue homeostasis, as well as in tumor development, by contributing to cell heterogeneity, plasticity, and development of drug resistance. The relationship between different types of normal and cancer stem cells is highly controversial and poorly understood. Here, we carried out gene expression network analysis of normal and tumor samples from genetically heterogeneous mice to create network metagenes for visualization of stem-cell networks, rather than individual stem-cell markers, at the single-cell level during multistage carcinogenesis. We combined this approach with lineage tracing and single-cell RNASeq of stem cells and their progeny, identifying a previously unrecognized hierarchy in which Lgr6+ stem cells from tumors generate progeny that express a range of other stem-cell markers including Sox2, Pitx1, Foxa1, Klf5, and Cd44. Our data identify a convergence of multiple stem-cell and tumor-suppressor pathways in benign tumor cells expressing markers of lineage plasticity and oxidative stress. This same single-cell population expresses network metagenes corresponding to markers of cancer drug resistance in human tumors of the skin, lung and prostate. Treatment of mouse squamous carcinomas in vivo with the chemotherapeutic cis-platin resulted in elevated expression of the genes that mark this cell population. Our data have allowed us to create a simplified model of multistage carcinogenesis that identifies distinct stem-cell states at different stages of tumor progression, thereby identifying networks involved in lineage plasticity, drug resistance, and immune surveillance, providing a rich source of potential targets for cancer therapy. One-Sentence SummaryGenes act in networks to drive cancer, and we identify these groups of genes from bulk-tissue and trace them at single-cell resolution.

cancer biology↗

bioRxiv2021

The YAP/TAZ antagonist, PTPN14, stabilizes SMAD4 through direct interactions in endothelial cells: Implications for Hereditary Hemorrhagic Telangiectasia

Hereditary Hemorrhagic Telangiectasia (HHT) results from germline loss-of-function mutations of ENG, ACVRL1, or SMAD4, encoding TGF{beta}/BMP signaling components. Telangiectasias occur in most patients, and pulmonary, visceral, or cerebral arteriovenous malformations (AVMs) in 20-50% of these. How HHT mutations cause these clinical manifestations and why some patients suffer more serious sequelae than others is unknown. PTPN14 is a genetic modifier of pulmonary AVM incidence, and here we show by gene expression network analysis of a large panel of genetically diverse mouse lung RNA samples, that Ptpn14 is ontologically associated with markers of angiogenesis, vascular remodeling, and BMP/TGF{beta} and Rho kinase signaling. We demonstrate physical interaction between protein tyrosine phosphatase non-receptor, type 14 (PTPN14) and SMAD4 in nucleus and cytoplasm of primary human endothelial cells. PTPN14 suppresses ubiquitination and turnover of SMAD4 to augment tonic SMAD-mediated transcriptional readouts. This is the first report that PTPN14 binds and stabilizes SMAD4, a key component of the HHT signaling pathway. Through this mechanism, and its inhibition of YAP/TAZ signaling, PTPN14 levels may protect against development of AVMs in HHT. We discuss potential druggable targets for HHT within the ENG-ALK1-SMAD4-PTPN14 network. One Sentence SummaryPTPN14 binds and stabilizes SMAD4 to potentiate BMP9 signaling in endothelial cells and components of the PTPN14 network may be drug targets for HHT.

cell biology↗

bioRxiv2019

Regulation of KRAS4A/B splicing in cancer stem cells by the RBM39 splicing complex.

The KRAS oncogene is expressed as major KRAS4B and minor KRAS4A splice isoforms, the distinct functions of which in cancer are unknown. We demonstrate here that KRAS4A is enriched in cancer stem-like cells, and is activated by hypoxia, whereas KRAS4B is more widely expressed and responds to ER stress. Mice completely lacking either isoform are viable but resistant to lung cancer development, as are Kras4A/B double heterozygous mice expressing both isoforms, but in which splice regulation has been uncoupled. Splicing of KRAS4A, but not KRAS4B, in human tumor cells can be inhibited by treatment with the splice inhibitor indisulam, or by CRISPR/Cas inhibition of the RBM39 splicing complex. Our data suggest that control of KRAS4A/B splicing is a targetable vulnerability in KRAS mutant tumors.

cancer biology↗

bioRxiv2019

Integration of pathway, cellular and genetic context reveals principles of synthetic lethality that affect reproducibility

Synthetic lethal screens have the potential to identify new vulnerabilities incurred by specific cancer mutations but have been hindered by lack of agreement between studies. Using KRAS as a model, we identified that published synthetic lethal screens significantly overlap at the pathway rather than gene level. Analysis of pathways encoded as protein networks identified synthetic lethal candidates that were more reproducible than those previously reported. Lack of overlap likely stems from biological rather than technical limitations as most synthetic lethal phenotypes were strongly modulated by changes in cellular conditions or genetic context, the latter determined using a pairwise genetic interaction map that identified numerous interactions that suppress synthetic lethal effects. Accounting for pathway, cellular and genetic context nominates a DNA repair dependency in KRAS-mutant cells, mediated by a network containing BRCA1. We provide evidence for why most reported synthetic lethals are not reproducible which is addressable using a multi-faceted testing framework.\n\nSTATEMENT OF SIGNIFICANCESynthetic lethal screens have the power to identify new targets in cancer, although have thus far come up short of expectation. We use computational and experimental approaches to delineate principles for identifying robust synthetic lethal targets that could aid in the development of effective new therapeutic strategies for genetically defined cancers.

cancer biology↗