Buckley, N. E. | Search bioRxiv

bioRxiv2026

Biological Signaling Pathways Associated with Late Tendon Development in Chicken Embryos and Their Dependence on Mechanical Stimulation

During embryonic and neonatal development, tendons exhibit rapid changes in mechanics and structure, including increases in collagen content, crosslinking, and fibril length. These functional and structural changes are partly dependent on mechanical stimulation. However, the specific mechanobiological mechanisms driving these changes remain poorly understood. The objective of this study was to identify the potential biological mechanisms and pathways driving tendon maturation into load-bearing materials using an embryonic chick model. Using bulk RNA sequencing, gene set enrichment analysis, and transcription factor analysis, we produced a transcriptomic profile of chick hindlimb tendons during late embryonic development (E16, E18, and E20) and tendons from rigid and flaccid paralysis-treated embryos. Additionally, we assessed the results from two differential expression analysis models to improve the replicability of our findings. Our results suggest that the largest transcriptomic response occurs between embryonic day 16 and 20, and that among paralysis conditions, rigid paralysis produces the greatest effect relative to controls. Across development, we found positive enrichment in processes related to mechanotransduction, extracellular matrix remodeling, cell adhesion, and contractility, and identified candidate pathways upregulated with development, including TGF-{beta}, PI3K-AKT-mTOR, Hippo, circadian rhythm, and focal adhesion signaling. In paralysis-treated embryos, our data suggest impairment in extracellular matrix remodeling and mechanotransduction events. Specifically, we found that both modes of paralysis are associated with a cellular stress response and downregulation of WNT signaling. Together, our findings identify candidate mechanotransduction pathways that are associated with late tendon maturation and altered by paralysis, which may inform tendon tissue engineering and regenerative approaches.

bioengineering↗

bioRxiv2020

The clinical and molecular significance associated with STING signaling in estrogen receptor-positive early breast cancer

STING signaling in cancer is a crucial component of response to immunotherapy and other anti-cancer treatments. Conversely, STING signaling can promote tumor invasion and metastasis. Currently, there is no robust method of measuring STING activation in cancer. Here, we describe an immunohistochemistry-based assay with digital pathology assessment of STING in tumor cells. Using this novel approach, we identify perinuclear-localized expression of STING (pnSTING) in estrogen receptor-positive (ER+) breast cancer as an independent predictor of good prognosis, associated with immune cell infiltration and upregulation of immune checkpoints. Tumors with low pnSTING are immunosuppressed with increased infiltration of "M2" -polarised macrophages. In ER-disease, pnSTING does not have a significant prognostic role, and STING appears to be uncoupled from interferon responses. Importantly, a gene signature defining low pnSTING expression in ER+ disease is predictive of poor prognosis in independent datasets. Low pnSTING is associated with chromosomal instability, MYC amplification and mTOR signaling, suggesting novel therapeutic approaches for this subgroup.

cancer biology↗