Abstract

Tumor metastasis is the primary cause of death of cancer patients. Therefore development of new therapeutics preventing tumor metastasis is urgently needed. Migrastatin is a natural product secreted by Streptomyces, and some of the synthesized migrastatin analogues are potent inhibitors of tumor cell migration in vitro and tumor metastasis in vivo. Here we show that these migrastatin analogues target the actin-bundling protein fascin to inhibit tumor metastasis. X-ray crystal structures of fascin in the absence and in the presence of a migrastatin analogue demonstrate that migrastatin analogues bind to fascin in a groove that has been biochemically and genetically defined as the surface for actin binding. By direct competing with the binding of F-actin to fascin, these migrastatin analogues inhibit fascin's actin-bundling activity. We show that fascin plays an essential role in tumor cell migration in vitro and tumor metastasis in vivo. Furthermore, fascin is over-expressed in many types of metastatic tumors and its elevated expression has been associated with the aggressiveness of tumors. Thus, fascin is a new molecular target for cancer treatment, and inhibitors of fascin, such as migrastatin analogues, are potential therapeutics for preventing tumor metastasis.

Heterotrimeric G proteins are critical transducers of cellular signaling. Gα₁₃^-/- mice died at embryonic stage ∼9.5. Here we show that heterozygous Gα₁₃^+/- mice displayed defects in adult angiogenesis. Female Gα₁₃ ^+/- mice show a higher number of immature follicles and a lower density of blood vessels in mature corpus luteum comparing with Gα₁₃ ^+/+ mice. Furthermore, implanted tumors grew slower in Gα ₁₃^+/- host mice due to decreased tumor angiogenesis. Moreover, bone marrow-derived progenitor cells from Gα₁₃ ^+/+ mice, when reconstituted into irradiated Gα₁₃ ^+/- mice, rescued the failed growth of allografted tumors in Gα ₁₃^+/- mice. Hence, Gα₁₃ is haploinsufficient for adult angiogenesis, both in the female reproductive system and in tumor angiogenesis.