Senescent cells and macrophages cooperate through a multi-kinase signaling network to promote intestinal transformation in Drosophila.

Cellular senescence is a conserved biological process that plays a crucial and context-dependent role in cancer. The highly heterogeneous and dynamic nature of senescent cells and their small numbers in tissues make in vivo mechanistic studies of senescence challenging. As a result, how multiple senescence-inducing signals are integrated in vivo to drive senescence in only a small number of cells is unclear. Here, we identify cells that exhibit multiple features of senescence in a Drosophila model of intestinal transformation, which emerge in response to concurrent activation of AKT, JNK, and DNA damage signaling within transformed tissue. Eliminating senescent cells, genetically or by treatment with senolytic compounds, reduces overgrowth and improves survival. We find that senescent cells promote tumorigenesis by recruiting Drosophila macrophages to the transformed tissue, which results in non-autonomous activation of JNK signaling. These findings identify senescent cell-macrophage interactions as an important driver of epithelial transformation.

The emerging role of LncRNA AWPPH in multiple cancers: a review study.

Long non-coding RNAs (lncRNAs) are transcribed RNA molecules longer than 200 nucleotides in length that have no protein-coding potential. They are able to react with DNA, RNA, and protein. Hence they involve in regulating gene expression at the epigenetic, transcriptional, post-transcriptional, and translational levels. LncRNAs have been proven to play an important role in human malignancies and prognostic outcomes. In this review, we will comprehensively and functionally discuss the role of a novel identified lncRNA, namely lncRNA WAPPH located on human chromosome 2q13, in various cancers. Increasing research studies have shown that lncRNA AWPPH is deregulated in different malignancies, including breast cancer, gastric cancer, colorectal cancer, ovarian cancer, bladder cancer, leukemia, and others. LncRNA WAPPH serves as an oncogene in tumorigenesis and the development of cancer. Moreover, lncRNA AWPPH is involved in numerous biological processes of solid and blood cancers. Taken together, based on our scrutiny analysis, lncRNA AWPPH can be regarded as a putative biomarker for diagnosis or therapeutic target in human malignancies.

Senescent cells and macrophages cooperate through a multi-kinase signaling network to promote intestinal transformation in Drosophila.

Cellular senescence is a conserved biological process essential for embryonic development, tissue remodeling, repair, and a key regulator of aging. Senescence also plays a crucial role in cancer, though this role can be tumor-suppressive or tumor-promoting, depending on the genetic context and the microenvironment. The highly heterogeneous, dynamic, and context-dependent nature of senescence-associated features and the relatively small numbers of senescent cells in tissues makes in vivo mechanistic studies of senescence challenging. As a result, which senescence-associated features are observed in which disease contexts and how they contribute to disease phenotypes remain largely unknown. Similarly, the specific mechanisms by which various senescence-inducing signals are integrated in vivo to induce senescence and why some cells become senescent while their immediate neighbors do not are unclear. Here, we identify a small number of cells that exhibit multiple features of senescence in a genetically complex model of intestinal transformation we recently established in the developing Drosophila larval hindgut epithelium. We demonstrate that these cells emerge in response to concurrent activation of AKT, JNK, and DNA damage response pathways within transformed tissue. Eliminating senescent cells, genetically or by treatment with senolytic compounds, reduces overgrowth and improves survival. We find that this tumor-promoting role is mediated by Drosophila macrophages recruited to the transformed tissue by senescent cells, which results in non-autonomous activation of JNK signaling within the transformed epithelium. These findings emphasize complex cell-cell interactions underlying epithelial transformation and identify senescent cell-macrophage interactions as a potential druggable node in cancer.

MicroRNA-452: a double-edged sword in multiple human cancers

MicroRNAs (miRNAs) are small, noncoding RNAs with important functions in development, cell differentiation, and regulation of cell cycle and apoptosis. MiRNA expression is deregulated in various pathological processes including tumorigenesis and cancer progression through various mechanisms including amplification or deletion of miRNA genes, mutations, and epigenetic silencing and defects in the miRNA biogenesis machinery. Several studies have now shown abnormal miRNA profiles and proved their involvement in the initiation and progression of cancer. Since miR-452 has diverse roles (as suppressor or oncogene) in different cellular processes including epithelial–mesenchymal transition (EMT), proliferation, migration, and invasion, in this review we highlight a brief overview of the biological function and regulatory mechanism of miR-452 and its involvement as a potential biomarker for diagnosis and treatment of various cancer types (AU)

A targeted genetic modifier screen in Drosophila uncovers vulnerabilities in a genetically complex model of colon cancer.

Received on 16 January 2023; accepted on 21 February 2023Kinases are key regulators of cellular signal transduction pathways. Many diseases, including cancer, are associated with global alterations in protein phosphorylation networks. As a result, kinases are frequent targets of drug discovery efforts. However, target identification and assessment, a critical step in targeted drug discovery that involves identifying essential genetic mediators of disease phenotypes, can be challenging in complex, heterogeneous diseases like cancer, where multiple concurrent genomic alterations are common. Drosophila is a particularly useful genetic model system to identify novel regulators of biological processes through unbiased genetic screens. Here, we report 2 classic genetic modifier screens focusing on the Drosophila kinome to identify kinase regulators in 2 different backgrounds: KRAS TP53 PTEN APC, a multigenic cancer model that targets 4 genes recurrently mutated in human colon tumors and KRAS alone, a simpler model that targets one of the most frequently altered pathways in cancer. These screens identified hits unique to each model and one shared by both, emphasizing the importance of capturing the genetic complexity of human tumor genome landscapes in experimental models. Our follow-up analysis of 2 hits from the KRAS-only screen suggests that classical genetic modifier screens in heterozygous mutant backgrounds that result in a modest, nonlethal reduction in candidate gene activity in the context of a whole animal-a key goal of systemic drug treatment-may be a particularly useful approach to identify the most rate-limiting genetic vulnerabilities in disease models as ideal candidate drug targets.

MicroRNA-452: a double-edged sword in multiple human cancers.

MicroRNAs (miRNAs) are small, noncoding RNAs with important functions in development, cell differentiation, and regulation of cell cycle and apoptosis. MiRNA expression is deregulated in various pathological processes including tumorigenesis and cancer progression through various mechanisms including amplification or deletion of miRNA genes, mutations, and epigenetic silencing and defects in the miRNA biogenesis machinery. Several studies have now shown abnormal miRNA profiles and proved their involvement in the initiation and progression of cancer. Since miR-452 has diverse roles (as suppressor or oncogene) in different cellular processes including epithelial-mesenchymal transition (EMT), proliferation, migration, and invasion, in this review we highlight a brief overview of the biological function and regulatory mechanism of miR-452 and its involvement as a potential biomarker for diagnosis and treatment of various cancer types.