Hicks, J. M. | bioRxiv Science

bioRxiv2024

The Dual Roles of the CXCL10-CXCR3 Axis and Its Therapeutic Potential in Osteosarcoma

The CXCL10-CXCR3 axis is recognized for its dual role in tumor biology, promoting tumor growth and metastasis via autocrine signaling while also eliciting anti-tumor responses through paracrine signaling. However, its specific functions in osteosarcoma (OS), the most prevalent malignant bone tumor in children, remain poorly understood. Our previous research has demonstrated that elevated circulating CXCL10 levels correlate with poor prognosis in OS patients. Analysis of the TARGET OS RNAseq dataset revealed that high expression levels of CXCL10 or its receptor CXCR3 are associated with improved prognosis. Given the known role of CXCL10 in recruiting CXCR3+ immune cells to combat cancer, we further analyzed single-cell RNAseq data and found that CXCR3 is predominantly expressed in CD3+ T cell populations. These findings suggest that CXCL10 may also play a protective role in OS by recruiting anti-tumor immune cells. To elucidate the causal role of the CXCL10-CXCR3 axis in OS, we conducted in vitro phenotypic assays on three OS cell lines with and without CXCL10. The chemokine was found to enhance tumor cell migration and AKT phosphorylation. Utilizing a CRISPR-mediated CXCR3 deletion mutant, we demonstrated that the absence of CXCR3 significantly inhibited OS tumor growth and pulmonary metastasis in an orthotopic xenograft mouse model. Transfection with the CXCR3A isoform, but not the CXCR3B isoform, restored the migratory phenotype of the CXCR3 deletion mutant to levels comparable to the parental cell line. Additionally, pharmacological inhibition of CXCR3 with AMG487 markedly reduced OS cell migration in vitro and metastasis development in the orthotopic xenograft mouse model. Our research highlights the complex interplay of the CXCL10-CXCR3 axis in both tumor and immune cells. We propose a working model for the roles of the CXCL10-CXCR3 axis in OS, suggesting that targeting CXCR3 may be an effective strategy to inhibit OS metastasis, particularly in immune-cold OS subtypes.

cancer biology↗

bioRxiv2024

Noise schemas aid hearing in noise

Human hearing is robust to noise, but the basis of this robustness is poorly understood. Several lines of evidence are consistent with the idea that the auditory system adapts to sound components that are stable over time, potentially achieving noise robustness by suppressing noise-like signals. Yet background noise often provides behaviorally relevant information about the environment, and thus seems unlikely to be completely discarded by the auditory system. Motivated by this observation, we explored whether noise robustness might instead be mediated by internal models of noise structure that could facilitate the separation of background noise from other sounds. We found that detection, recognition, and localization in real-world background noise was better for foreground sounds positioned later in a noise excerpt, with performance improving over the initial second of exposure to a noise. These results are consistent with both adaptation-based and model-based accounts, since both explanations require online noise estimation that should benefit from acquiring more samples. However, performance was also robust to interruptions in the background noise and was enhanced for intermittently recurring backgrounds, neither of which would be expected from known forms of adaptation. Additionally, the performance benefit observed for foreground sounds occurring later within a noise excerpt was reduced for recurring noises, suggesting that a noise representation is built up during exposure to a new background noise and then maintained in memory. These findings suggest noise robustness is supported by internal models--"noise schemas"--that are rapidly estimated, stored over time, and used to estimate other concurrent sounds.

neuroscience↗