One of the defining characteristics of cancer cells is their ability to rapidly proliferate, evade the host immune system, invade the surrounding tissue, and metastasize to distant organs and tissues. Cancer cells often attain these aggressive characteristics by altering the function of normal cellular proteins to favor these activities. Cell signaling pathways, such as that of transforming growth factor-beta or TGF-beta, are often dysregulated to favor these aggressive characteristics during carcinogenesis. One of the emerging strategies in cancer treatment, especially for aggressive cancers such as metastatic breast, brain, and prostate cancer, is to therefore block proteins such as TGF-beta so the cancer cells can no longer misuse them. Our laboratory, which has studied TGF-beta structure and function for nearly 20 years, is working together to block TGF-beta by preventing it from interacting with its receptors, the critical first step in the TGF-beta signaling pathway. Our efforts in this regard have been made possible by the determination of the atomic level structure of TGF-beta bound to its receptors, which has shown how the different receptors are arranged relative to one another when they bind TGF-beta.
One of the most important steps in developing inhibitors for targeting TGF-beta is attaining an understanding of the essential interactions between TGF-beta and its receptors; once this knowledge is in hand, then screening strategies can be employed to identify inhibitors that target these critical sites and therefore block assembly of the TGF-beta signaling complex.
Our results obtained in the study recently reported by Zúñiga, et al. showed that one of the two receptors that are required for TGF-beta signaling – the so called TGF-beta type I receptor - has a distinctive loop region that protrudes from the protein and is key to forming interactions required for assembly of the full active signaling complex on the cell surface.
Our knowledge of these critical interactions has now allowed us to design a screen for small molecules and peptides that target this critical interaction – our hope is that this will yield novel inhibitors that can be used to block the tumor- and metastasis-promoting activity in advanced metastatic breast, brain, and prostate cancer where TGF-beta is known to driving tumor growth and metastasis.
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