Fascin Inhibitors Decrease Cell Migration and Adhesion While Increase Overall Survival of Mice Bearing Bladder Cancers

Abstract

Bladder cancer is one of the most common cancers in the world. Early stage bladder tumors can be surgically removed, but these patients usually have relapses. When bladder cancer becomes metastatic, survival is very low. There is an urgent need for new treatments for metastatic bladder cancers. Here, we report that a new fascin inhibitor decreases the migration and adhesion of bladder cancer cells. Furthermore, this inhibitor decreases the primary tumor growth and increases the overall survival of mice bearing bladder cancers, alone, as well as in combination with the chemotherapy medication, cisplatin, or the immune checkpoint inhibitor, anti-PD-1 antibody. These data suggest that fascin inhibitors can be explored as a new treatment for bladder cancers.

Inhibitors of the Actin-Bundling Protein Fascin-1 Developed for Tumor Therapy Attenuate the T-Cell Stimulatory Properties of Dendritic Cells

“…Altogether, our results confirm the necessity of performing comparative, in-depth in vivo studies employing distinct Fscn1 inhibitors and subsequent ex vivo analysis to delineate, in detail, by which mechanisms these may inhibit tumor growth. These mechanisms comprise inhibition of Fscn1-dependent tumor cell migration [ 19 , 20 , 21 , 48 ] and Fscn1-dependent gene expression in tumor cells [ 18 , 49 , 50 , 51 ], which may impact the characteristics of the TME, e.g., via soluble mediators. However, as shown in this study, Fscn1 inhibitors may also affect the immunophenotype and function of DCs and exert pronounced off-target effects on immune cells in an inhibitor-specific manner, as shown here for DCs and T cells.…”

“…Besides its structural properties, Fscn1 was also shown to actively translocate from the cytoplasm into the nucleus of tumor cells and to positively regulate expression of pro-tumorigenic genes, such as the amino-acid transporter solute carrier family 3 member 2 [ 17 ] and to promote pro-tumorigenic canonical wingless signaling via activation of activation of focal adhesion kinase [ 18 ]. To date, several Fscn1 inhibitors that block interaction of Fscn1 with F-actin in order to inhibit tumor metastasis have been developed and successfully evaluated in vitro and in preclinical models [ 19 , 20 , 21 ]. More recently, a clinical phase I trial demonstrated that oral application of a Fscn1 inhibitor was well-tolerated and demonstrated antimetastatic activity, with increased progression-free survival in a number of patients [ 22 ].…”

The role of fascin-1 in the pathogenesis, diagnosis and management of respiratory related cancers

“…Our previous study and many other studies revealed that fascin-1 can promote tumor cell migration, invasion, and metastasis (13). Our previous study and many other studies revealed that fascin-1 can promote tumor cell migration, invasion, and metastasis (13)(14)(15)(16). A growing number of studies have shown that it can be used as a new biomarker and therapeutic target and to assess the prognosis of cancer patients.…”

Lactate-mediated Fascin protrusions promote cell adhesion and migration in cervical cancer

“…Additionally, several studies have demonstrated that β-catenin plays a key role in regulating and coordinating intracellular adhesion via ligation between the cytoskeleton and membrane 13 - 15 , and the translocation of β-catenin into the nucleus up-regulates the transcriptional level of fascin 16 , 17 . Fascin inhibitors have been shown to efficiently block the migration of intratumoral dendritic cells and cancer growth in xenograft mouse model and clinical studies 8 , 12 , 18 - 20 . High lactate levels circulating in the blood have often been shown to increase the risk of metastasis of many cancers 21 - 23 , and our recent studies have shown that low concentrations of LA can trigger Epstein-Barr Virus (EBV)-immortalized B lymphoblastic cell adhesion by downregulating viral miRNA expression 24 .…”