Biology subjects

Guarnaccia, G.

Publications and source records attributed to Guarnaccia, G..

2 recordsLinked to original sources

bioRxiv2026

Tumor-derived SAA1-TLR4 signaling drives tumor-to-muscle communication in pancreatic cancer cachexia

Cancer cachexia limits treatment tolerance and survival in pancreatic ductal adenocarcinoma (PDAC), yet the tumor-derived signals driving tissue dysfunction remain poorly understood. Here, we identify serum amyloid A1 (SAA1) as a mediator of tumor-to-host communication acting through Toll-like receptor 4 (TLR4). Tumor-derived SAA1 was elevated in human PDAC and in a mouse PDAC model and disrupted both myofiber and muscle stem cell (MuSC) homeostasis. Genetic reduction of tumor-derived SAA1 uncoupled tumor progression from host wasting, preserving muscle mass and function and prolonging survival without affecting primary tumor growth. Mechanistically, SAA1-TLR4 signaling drove multicellular remodeling of the skeletal muscle microenvironment. Therapeutic TLR4 inhibition after cachexia onset restored muscle mass, function and MuSC abundance and prolonged survival independently of tumor growth. Conservation of SAA1-TLR4 signaling in human skeletal muscle identifies a therapeutically actionable tumor-host pathway and demonstrates that host deterioration can be targeted independently of tumor progression.

cancer biology↗

bioRxiv2024

Tenascin-C from the tissue microenvironment promotes muscle stem cell self-renewal through Annexin A2

Skeletal muscle tissue self-repair occurs through the finely timed activation of resident muscle stem cells (MuSC). Following perturbation, MuSC exit quiescence, undergo myogenic commitment, and differentiate to regenerate the injured muscle. This process is coordinated by signals present in the tissue microenvironment, however the precise mechanisms by which the microenvironment regulates MuSC activation are still poorly understood. Here, we identified Tenascin-C (TnC), an extracellular matrix (ECM) glycoprotein, as a key player in promoting of MuSC self-renewal and function. We show that fibro-adipogenic progenitors (FAPs) are the primary cellular source of TnC during muscle repair, and that MuSC sense TnC signaling through cell the surface receptor Annexin A2. We provide in vivo evidence that TnC is required for efficient muscle repair, as mice lacking TnC exhibit a regeneration phenotype of premature aging. We propose that the decline of TnC in physiological aging contributes to inefficient muscle regeneration in aged muscle. Taken together, our results highlight the pivotal role of TnC signaling during muscle repair in healthy and aging skeletal muscle.

cell biology↗