A group of researchers partly funded by the TFRI has found that all cancers can be classified into two distinct groups based on the presence of a protein known as YAP. These two groups – YAPon cancers and YAPoff cancers – were also found to respond to drugs differently, opening the door for the creation of treatment plans that take YAP status into consideration.
“A major goal of studying any complex system is to find rules that underpin its behaviour,” said Dr. Rod Bremner, the paper’s senior author and a senior investigator at the Lunenfeld-Tanenbaum Research Institute, part of Sinai Health in Toronto. “We hope that the simple YAP binary rule will provide better understanding of cancer behaviour.”
We reached out to Dr. Bremner to learn more about this fascinating finding:
TFRI: What would you highlight as the most important finding of this paper?
RB: Cancer is incredibly complex because it can arise from many different combinations of gene defects. Even within the same tumour there are different groups of cells with distinct combinations of defects. Despite this complexity, we found an overarching rule that simplifies all cancers into just two types. What is more surprising though, is that these two classes are defined by the same protein, YAP. In one group, YAP is present and essential for tumour growth (YAPon cancers). In the other, however, YAP is switched off because it has the opposite anti-cancer function, blocking tumour growth (YAPoff cancer). Thus, binary classes are defined by opposite levels and opposite pro- or anti-cancer activity of the same protein.
How is this finding helping to advance the science of cancer?
A major goal of studying any complex system is to find rules that underpin its behaviour. Simple, far-reaching rules provide new perspectives. Imagine an alien trying to understand how airports work. At first glance, it’s a melee of confusion with dozens of planes and thousands of people. An overarching principle, however, is that there are arrivals and departures. Viewed through that lens, a complicated system is easier to understand. We hope that the simple YAP binary rule will provide better understanding of cancer behaviour.
What foreseeable impact could this discovery have on cancer patients?
We showed the binary cancer classes have distinct drug sensitivities. Thus, drugs that are effective against YAP-deficient cancers are not effective against YAP-positive cancers, and vice versa. This discovery opens up new possibilities for optimizing therapeutics for any cancer, depending on which class it falls into. It also offers a launching pad to find drug combinations that are even more effective than any of the single drugs.
The contrasting drug sensitivities of the two classes suggested that switching from one binary type to the other might help cancers escape therapy. Indeed, we showed that lung and prostate cancer can switch from the YAPon to the YAPoff class. That switch creates a highly lethal drug-resistant form of cancer for which there is no treatment. Our data suggest potential new approaches to treat these cancers.
Is there anything else you think is important to highlight about this paper?
We didn’t set out to discover a pan-cancer rule. We were trying to understand why defects in a tumour suppressor gene called RB1 causes cancer in some cell types, but not others. We focussed first on a rare childhood eye tumour called retinoblastoma, which is caused by loss of RB1. We were surprised to find that these tumours lack YAP, but rare, benign and harmless regions in these tumours (“retinoma”) were YAP-positive. That, along with counter-intuitive results in our mouse models of retinoblastoma, set us off on the path to find other tumours like it. This curiosity exposed a long list of YAPoff cancers and the binary rule. Despite being a relatively unfashionable cancer due to its rarity, retinoblastoma has a rich history of exposing broadly relevant cancer principles. And that story highlights another overarching rule: curiosity is always a better guide than popularity in discovery science.
Image: Dr. Rod Bremner (right) poses with the first author of the paper, Dr. Joel Pearson
Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/ TEAD activity
Joel D Pearson, Katherine Huang, Marek Pacal, Sean R McCurdy, Suying Lu, Arthur Aubry, Tao Yu, Kristine M Wadosky, Letian Zhang, Tao Wang, Alex Gregorieff, Mohammad Ahmad, Helen Dimaras , Ellen Langille, Susan P C Cole, Philippe P Monnier, Benjamin H Lok, Ming-Sound Tsao, Nagako Akeno, Daniel Schramek, Kathryn A Wikenheiser-Brokamp, Erik S Knudsen, Agnieszka K Witkiewicz, Jeffrey L Wrana, David W Goodrich, Rod Bremner
This study was partially funded by a Terry Fox New Frontiers Program Project Grant to Targeting the Hippo Signalling Pathway in Cancer