AI-guided S100A4-targeting peptides suppress pancreatic cancer metastasis by blocking collective invasion

Pancreatic ductal adenocarcinoma (PDAC) is an exceptionally lethal malignancy, characterized by aggressive biology and a severe lack of effective therapeutic options. A critical aspect of its progression is collective invasion, where tumor cells invade surrounding tissues as multicellular units, maintaining cell-cell interactions. Current treatments often fail due to early metastasis and the complex tumor microenvironment. The S100-family proteins, previously identified as upregulated in the PDAC secretome, are implicated in these processes, but their specific roles in collective invasion and metastasis remained to be fully elucidated. This study investigates S100A4's contribution to these mechanisms.

Researchers established a 3D collective invasion model using co-culture spheroids of PDAC cells and pancreatic stellate cells (PSCs). They manipulated S100A4 expression via knockdown and overexpression to assess its impact on collective invasion, trans-endothelial migration, and cancer cell adhesion. An orthotopic pancreatic tumor model was used to evaluate histological tumor aggressiveness and metastasis after S100A4 depletion. Finally, de novo S100A4-targeting inhibitory peptides were developed using AI-guided structure modeling, with their inhibitory effects on collective invasion confirmed in the 3D spheroid model.

S100A4 was identified as a key mediator of collective invasion, specifically by facilitating interactions between PDAC cells and PSCs. > S100A4 knockdown significantly inhibited collective invasion, while its overexpression actively promoted this aggressive cellular behavior in the 3D co-culture model. Furthermore, depletion of S100A4 in PDAC cells reduced trans-endothelial migration and decreased cancer cell adhesion to endothelial cells, both critical steps in the metastatic cascade. Mechanistically, extracellular S100A4 derived from PDAC cells was found to promote LAMB3 expression in PSCs, highlighting a novel signaling pathway in the tumor microenvironment. In the orthotopic pancreatic tumor model, S100A4 depletion significantly reduced histological tumor aggressiveness and inhibited metastasis, underscoring its crucial role in vivo. The AI-guided de novo S100A4-targeting inhibitory peptides successfully demonstrated inhibitory effects on collective invasion in vitro, validating their therapeutic potential. No specific percentages or p-values were provided in the abstract.