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Cancer is a heterogeneous genetic disease notorious for dodging several bullets of treatments. Tumors can develop in different organs and tissues of the body. As a result, there are over 100 types of cancers according to the National Cancer Institute. One of the current approaches pursued to solve cancer complexity is developing a comprehensive stratification. This approach guides optimal treatment that can be tailored to a particular cancer type. The stratifications can be based on either cell patterns or molecular composition. A recent study released by scientists at the Lunenfeld-Tanenbaum Research Institute suggested that all types of cancer can be categorized into two types based on the presence/absence of the YAP protein.
YAP, also known as Yes-Associated Protein or TAZ, is a protein that controls the expression genes that drive the progression of several cancers. Discovered in 1994, YAP is one of the key players in the Hippo signaling pathway. It is associated with other proteins that serve as coactivators of gene expression such as the TEAD proteins. Under normal conditions, when the Hippo signaling pathway is activated, a series of phosphorylation cascades lead to the degradation of YAP. In this way, the transport of YAP into the nucleus, and consequently activation of gene transcription, is blocked. In cancer, the reverse occurs because the Hippo signaling pathway is mostly in an off-state. Together with TEAD, YAP activates the expression of approximately 100 genes. Interestingly, the role of YAP has an additional layer of complexity in cancers. It could function as an accomplice in cancer progression or as a guard against it.
A recent study released by scientists at the Lunenfeld-Tanenbaum Research Institute suggested that all types of cancer can be categorized into two types based on the presence/absence of the YAP protein. After surveying over 1000 cancer cell types, the researchers discovered that the dual expression and opposite function of the YAP protein distinctively classify most cancers. For instance, low YAP levels were observed in all blood cancers and a subset of solid cancers that are neuroendocrine in nature including breast, pancreas, and small cell lung cancer. On the other hand, other solid cancers were shown to have high YAP levels.
The presence of YAP in YAP off cancers promotes cell death in cancer cells. It also drives the expression of adhesive genes and inhibits cell growth and multiplication. This tumor-suppressive feature of YAP in YAP off cancers was revealed to be facilitated by a YAP target protein called Integrin-B5. Interestingly, one characteristic of most of the YAP off cancers is that they are non-adherent. So, the overexpression of YAP in YAP off cancers would be a great therapeutic strategy to cause tumor regression in this particular cancer class. On the other hand, reducing the levels of YAP in YAP on cancers is more effective. In this class of cancers, YAP binds to a different set of co-activators to induce the expression of cell growth genes.
This opposite function of YAP on/off cancers prompted researchers to examine the susceptibility of either cancer type to certain classes of drugs. Following extensive database mining and analysis, they discovered that YAP off cancers are inhibited by drugs that target anti-apoptotic proteins(BcLs), chromatin remodeling enzymes (HDAC), and translation proteins (EIF4). In contrast, YAP on cancers is more vulnerable to drugs that target tyrosine and serine/threonine kinases.
The findings from this study highlight the importance of sub-classifying cancers based on molecular composition. It exposed distinct vulnerabilities in several cancers that can be wielded as a weapon against cancer. Particularly, the number of years spent in developing certain therapeutics can be reduced with the knowledge of such vulnerabilities. Also, patients can benefit from the personalized treatment approach driven by understanding gene dependencies in their particular cancer type. Hence, increased efforts should be geared towards stratifying cancers with common underlying targets that drive cancer progression.
Edited by Payal Yokota
- Pearson, J. D., Huang, K., Pacal, M., McCurdy, S. R., Lu, S., Aubry, A., … & Bremner, R. (2021). Binary pan-cancer classes with distinct vulnerabilities defined by pro-or anti-cancer YAP/TEAD activity. Cancer Cell, 39(8), 1115-1134.
- Sántha, P., Lenggenhager, D., Finstadsveen, A., Dorg, L., Tøndel, K., Amrutkar, M., … & Verbeke, C. (2021). Morphological Heterogeneity in Pancreatic Cancer Reflects Structural and Functional Divergence. Cancers, 13(4), 895.
- Cancer stratification: A systems approach · Institute for Systems Biology. Institute for Systems Biology. (2019, May 10). Retrieved October 28, 2021, from https://isbscience.org/news/2014/05/12/cancer-stratification-a-systems-approach/.
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