Loss of ASAP1 in the MMTV-PyMT model of luminal breast cancer activates AKT, accelerates tumorigenesis, and promotes metastasis.

ASAP1 is a multi-domain adaptor protein that regulates cytoskeletal dynamics, receptor recycling and intracellular vesicle trafficking. Its expression is associated with poor prognosis in a variety of cancers, and can promote cell migration, invasion and metastasis. Although amplification and expression of ASAP1 has been associated with poor survival in breast cancer, we found that in the autochthonous MMTV-PyMT model of luminal breast cancer, ablation of ASAP1 resulted in an earlier onset of tumor initiation and increased metastasis. This was due to tumor cell-intrinsic effects of ASAP1 deletion, as ASAP1 deficiency in tumor, but not in stromal cells was sufficient to replicate the enhanced tumorigenicity and metastasis observed in the ASAP1-null MMTV-PyMT mice. Loss of ASAP1 in MMTV-PyMT mice had no effect on proliferation, apoptosis, angiogenesis or immune cell infiltration, but enhanced mammary gland hyperplasia and tumor cell invasion, indicating that ASAP1 can accelerate tumor initiation and promote dissemination. Mechanistically, these effects were associated with a potent activation of AKT. Importantly, lower ASAP1 levels correlated with poor prognosis and enhanced AKT activation in human ER+/luminal breast tumors, validating our findings in the MMTV-PyMT mouse model for this subtype of breast cancer. Taken together, our findings reveal that ASAP1 can have distinct functions in different tumor types and demonstrate a tumor suppressive activity for ASAP1 in luminal breast cancer.

A hybrid scaffold of gelatin glycosaminoglycan matrix and fibrin as a carrier of human corneal fibroblast cells.

A hybrid scaffold of gelatin-glycosaminoglycan matrix and fibrin (FGG) has been synthesized to improve the mechanical properties, degradation time and cell response of fibrin-like scaffolds. The FGG scaffold was fabricated by optimizing some properties of fibrin-only gel and gelatin-glycosaminoglycan (GG) scaffolds. Mechanical analysis of optimized fibrin-only gel showed the Young module and tensile strength of up to 72 and 121 KPa, respectively. Significantly, the nine-fold increase in the Young modulus and a seven-fold increase in tensile strength was observed when fibrin reinforced with GG scaffold. Additionally, the results demonstrated that the degradation time of fibrin was enhanced successfully up to 7 days which was much longer time compared to fibrin-only gel with 38 h of degradation time. More than 45% of FGG initial mass was preserved on day 7 in the presence of aprotinin. Human corneal fibroblast cells (HCFCs) were seeded on the FGG, fibrin-only gel and GG scaffolds for 5 days. The FGG scaffold showed excellent cell viability over 5 days, and the proliferation of HCFCs also increased significantly in comparison with fibrin-only gel and GG scaffolds. The FGG scaffold illustrates the great potential to use in which appropriate stability and mechanical properties are essential to tissue functionality.