A groundbreaking study published in Nature revealed the important role of secreted phosphoprotein 1 (SPP1), also known as osteopontin, in the pathogenesis of pancreatic ductal adenocarcinoma (PDAC). The research highlights how SPP1 promotes tumor aggressiveness and identifies potential treatment interventions targeting this protein.
Pancreatic cancer is one of the cancers with the lowest chances of survival rates, and its 5-year survival rate is only 13%. Intratumor heterogeneity is a characteristic feature of PDAC, as tumors typically harbor both epithelial-like and mesenchymal-like cancer cell populations. This variability contributes to the disease aggressiveness through mechanisms that remain incompletely understood.
Researchers compared blood samples from patients with PDAC. They found that the levels of SPP1 were significantly higher in those patients with stages of the disease (stages III and IV) compared to early stages (stages I and II). The same results were observed in KPCY mouse models; specifically, elevated plasma SPP1 levels were found in tumor-bearing mice compared to normal mice. This suggests that SPP1 is strongly associated with tumor progression.
Using CRISPR-Cas9 to delete the Spp1 gene in PDAC organoids. They found that the loss of mesenchymal VIM-GFP+ cells was accompanied by cells adopting more epithelial properties. These organoids, when implanted into mice, resulted in smaller tumor sizes dominated by epithelial cells in the case of Spp1-deficient tumors and larger tumors containing a combination of cells in the case of control organoids. This demonstrates that SPP1 plays a role in sustaining aggressive mesenchymal tumor cells.
Molecular analysis revealed that SPP1, secreted by epithelial cells, binds to CD61 (Itgb3) on mesenchymal cells, triggering the expression of BMP2 and GREM1. GREM1 inhibits BMP signaling, and this inhibition is required to maintain SPP1 expression in epithelial cells. This together, constitutes a feedback loop that maintains the cells in both the epithelial and mesenchymal states. Interestingly, Itgb3 knock-out produced the same phenotype as Spp1 deletion, confirming its importance.
Animal studies showed a biological effect. The deletion of Spp1 in KPFCT mouse models caused tumors to acquire an epithelial-like identity, and metastases to the liver and lung were significantly reduced, resulting in prolonged survival. Spp1 knockout prevented visible metastases in the KPhetFCT model, which was highly metastatic (23% of livers and 30% of lungs) with wild-type tumors. An SPP1 blocking antibody treatment also decreased mesenchymal cell fate and inhibited metastasis, suggesting a potential therapeutic application.
Further analysis showed that SPP1 regulates BMP2 and GREM1 through NF-kappaB signaling. A combination of SPP1, BMP2, and GREM1 constitutes a regulatory circuit that regulates the cell fate of PDAC. Interdependence was verified by double knock-out experiments. The deletion of Grem1 reversed the epithelial reprogramming induced by the deletion of Spp1, thereby restoring the mesenchymal phenotype. Effects of Spp1 loss were also moderated by Grem1 heterozygosity, highlighting interdependent regulation.
The study concluded that PDAC tumor heterogeneity arises from paracrine interactions between mesenchymal and epithelial cells. Additionally, the SPP1-CD61-GREM1-BMP2 axis could be targeted to decrease heterogeneity, prevent metastasis, and improve survival. These findings establish SPP1 as a key regulator of the mesenchymal state in PDAC, indicating that inhibiting this pathway can reprogram tumors into less aggressive states. The discovery of this pathway presents a promising avenue for future therapeutic strategies in one of the most devastating forms of cancer globally.
References: Li H, Lan L, Chen H, et al. SPP1 is required for maintaining mesenchymal cell fate in pancreatic cancer. Nature. 2025. doi:10.1038/s41586-025-09574-y
