Hammad, M. | Search bioRxiv

bioRxiv2026

Tumor-Intrinsic IL-17 Signaling Correlates with Multimodal Resistance Phenotypes Following Oncolytic Adenovirus Challenge

Oncolytic adenovirus (ADV) therapy faces heterogeneous responses, implying tumor-intrinsic resistance. We identify interleukin-17 (IL-17) signaling as a novel potential barrier associated with multi-modal cellular reprogramming. Transcriptomic analysis of ADV-treated 4T1 murine mammary carcinoma cells revealed specific upregulation of Il17rb, Il17rd, and Il17f, indicating viral induction of this inflammatory axis. The IL-17 signature correlates strongly with a cancer stemness phenotype. Metabolically, it associates with increased lipid metabolism and suppressed glycolysis, suggesting a state resistant to viral replication. Furthermore, it broadly negatively correlates with programmed cell death pathways (apoptosis, necrosis) while positively associating with pro-survival autophagy. IL-17 component expression effectively stratifies samples into distinct metastatic risk categories, underscoring its prognostic potential. Our findings reveal a previously unrecognized, tumor-intrinsic role for IL-17 signaling in ADV resistance, associated with enhanced stemness, altered metabolism, and impaired cell death. This nominates the IL-17 pathway as both a predictive biomarker and a therapeutic target for combination strategies. HighlightsO_LIOncolytic adenovirus infection selectively upregulates IL-17 receptor subunits (IL17RB, IL17RD) and IL17F ligand in 4T1 tumor cells C_LIO_LIIL-17 receptor expression strongly correlates with cancer stemness gene signatures, particularly through IL17RB and IL17RD C_LIO_LIThe IL-17 axis associates with broad suppression of lytic cell death pathways (apoptosis, necrosis, necroptosis) while positively correlating with autophagy C_LIO_LIIL-17 pathway activity correlates with metabolic reprogramming favoring lipid turnover over glycolysis C_LIO_LIIL-17 expression levels stratify samples into distinct metastatic risk categories, suggesting biomarker potential C_LI

cancer biology↗

bioRxiv2026

Lyophilized Cell-Secreted Matrix as a Bioactive Substrate for Chondrocyte Expansion and Redifferentiation

Articular cartilage repair is limited by the poor regenerative capacity of chondrocytes and their rapid dedifferentiation during in vitro expansion. This study investigated whether a decellularized and lyophilized cell-secreted matrix (CSM) could function as a bioactive material to regulate cell behavior, promote chondrogenic differentiation, and attenuate or reverse chondrocyte dedifferentiation without exogenous growth factor supplementation. CSM was generated from rabbit auricular perichondrial cells, decellularized, lyophilized, and characterized by histology, biochemical assays, and proteomic analysis. The resulting matrix was enriched in structurally and functionally relevant extracellular matrix proteins, including collagens, fibronectin, fibrillin, proteoglycans, and matricellular regulators, with minimal intracellular contamination and good batch-to-batch reproducibility. Functionally, CSM supported robust adhesion and proliferation of allogeneic and xenogeneic cells. Human articular chondrocytes cultured on CSM exhibited enhanced proliferation, sustained expression of cartilage-specific markers, and preserved type II collagen production over serial passages compared with standard plastic culture. CSM also promoted chondrogenic differentiation of human progenitor cells and partially reversed established chondrocyte dedifferentiation, as evidenced by increased expression of COL2A1, ACAN, SOX9, and COMP, with reduced COL1 expression and no induction of hypertrophic markers. These findings demonstrate that lyophilized CSM is a stable, off-the-shelf biomaterial capable of directing chondrocyte fate through intrinsic matrix-derived cues, highlighting its potential for cartilage tissue engineering and cell manufacturing applications.

bioengineering↗