Xiaodong Jin

A pivotal objective in clinical research is to transition the abscopal effect in radiotherapy from a stochastic to a deterministic phenomenon. In this study, leveraging a mouse breast cancer model, we discovered that during the manifestation of radiation-induced abscopal effects (RIAE), Fibronectin 1 (FN1) expression experienced a marked downregulation in macrophages within the distant tumor microenvironment. Our experimental findings revealed that the downregulation of FN1 skewed macrophages towards the pro-inflammatory M1 phenotype through the PI3K/Akt pathway, augmenting their phagocytic abilities and fostering the proliferation and activation of CD8 + T cells. The outcomes from both cellular and animal experiments underscored the potential of inhibiting FN1 expression to reduce the threshold for RIAE occurrence, effectively transforming it from a random effect into a predictable one. Significantly, our study demonstrated that Avapritinib, a KIT/PDGFRA kinase inhibitor approved by the U.S. Food and Drug Administration (FDA), effectively suppressed FN1 and facilitated RIAE. This finding unveils previously unrecognized translational prospects for clinical radiotherapy.

Tumor protein 73 antisense RNA 1 (TP73-AS1), a newly discovered long non-coding RNA (lncRNA), the dysregulated expression of which is closely related to the occurrence, drug resistance, and prognosis of various cancers. Exploring the regulatory mechanism of TP73-AS1 provides a new research direction for cancer diagnosis and treatment. On this basis, we briefly review the molecular structural and dual regulatory roles of TP73-AS1 in cancer. In addition, we outline its three molecular mechanisms in cancer: binding to proteins, regulating signaling pathways, and serving as molecular sponges. Subsequently, we introduce the role of TP73-AS1 in common malignant tumors such as gastric cancer (GC), lung cancer, colorectal cancer (CRC), etc. Last, emphasis is given to the potential clinical value of TP73-AS1, especially as single nucleotide polymorphisms of this lncRNA are associated with the risk of GC and CRC. Therefore, this review highlights the significance of TP73-AS1 as a novel biomarker and therapeutic target.

Increased stemness of cancer cells exacerbates radioresistance, thereby greatly limiting the efficacy of radiotherapy. In order to study the changes in cancer cell stemness during radiotherapy, we established a radioresistance model of human non-small cell lung cancer A549 cells and obtained A549 radioresistant cells (A549-RR). We sampled the cells at different time points during the modeling process and investigated the heterogeneity of each group of cells using single-cell sequencing. Cells in the early stages of fractionated irradiation were found to be significantly up-regulated in stemness, and a subpopulation of cells producing this response was screened and referred to as “radiation-induced stemness-responsive cancer cells”. They were undergoing stemness response, energy metabolism reprogramming, and progressively differentiating into cells with more diverse and malignant phenotypes in order to attenuate the killing effect of radiation. Furthermore, we demonstrated that such responses might be driven by the activation of the EGFR-Hippo signaling pathway axis, which also plays a crucial role in the development of radioresistance. Our study reveals the dynamic evolution of cell subpopulation in cancer cells during fractionated radiotherapy; the early stage of irradiation can determine the destiny of the radiation-induced stemness-responsive cancer cells. The activation of stemness-like phenotypes during the development of radioresistance is not the result of dose accumulation but occurs during the early stage of radiotherapy with relatively low-dose irradiation. The degree of the radiation-induced stemness response of cancer cells mediated by the EGFR-Hippo signaling pathway might be a potential predictor of the efficacy of radiotherapy and the development of radioresistance.

Long non-coding RNAs (LncRNAs) are a class of RNA molecules with nucleic acid lengths ranging from 200 bp to 100 kb that cannot code for proteins, which are diverse and widely expressed in both animals and plants. Scholars have found that lncRNAs can regulate human physiological processes at the gene and protein levels, mainly through the regulation of epigenetic, transcriptional and post-transcriptional levels of genes and proteins, as well as in the immune response by regulating the expression of immune cells and inflammatory factors, and thus participate in the occurrence and development of a variety of diseases. From the downstream targets of lncRNAs, we summarize the new research progress of lncRNA mechanisms other than miRNA sponges in recent years, aiming to provide new ideas and directions for the study of lncRNA mechanisms.

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