Biology subjects

Cecchini, A.

Publications and source records attributed to Cecchini, A..

3 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

Ephrin-A5 and EphA7 stimulation is anti-proliferative for human rhabdomyosarcoma in vitro

Rhabdomyosarcoma (RMS) is a tumor which resembles skeletal muscle. Current treatments are limited to surgery and non-targeted chemotherapy, highlighting the need for alternative therapies. Differentiation therapy uses molecules that act to shift the tumor cells phenotype from proliferating to differentiated, which in the case of skeletal muscle includes exit from the cell cycle and potentially fusion into myofibers. We previously identified EphA7 expressed on terminally differentiated myocytes as a potent driver of skeletal muscle differentiation: stimulation of ephrin-A5-expressing myoblasts with EphA7 causes them to undergo rapid, collective differentiation. We therefore tested EphA7 as a candidate molecule for differentiation therapy on human RMS (hRMS) cell lines. Surprisingly, EphA7 had a lesser effect than ephrin-A5, a difference explained by the divergent suite of Ephs and ephrins expressed by hRMS. We show that in hRMS ephrin-A5 binds and signals to EphA8 and EphA7 binds and signals to ephrin-A2, and that Fc chimeras of both molecules are potent inhibitors of hRMS proliferation. These results identify key differences between hRMS and normal muscle cells and support further research into Eph:ephrin signaling as potential differentiation therapies. Summary statementThis study identifies EphA7 and ephrin-A5 as external regulators of rhabdomyosarcoma proliferation, highlighting ephrin-A5 as a potential candidate for differentiation therapy in future cancer treatments.

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↗