AUTHOR=Weisman Caroline M. TITLE=The permissive binding theory of cancer JOURNAL=Frontiers in Oncology VOLUME=13 YEAR=2023 URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1272981 DOI=10.3389/fonc.2023.1272981 ISSN=2234-943X ABSTRACT=

The later stages of cancer, including the invasion and colonization of new tissues, are actively mysterious compared to earlier stages like primary tumor formation. While we lack many details about both, we do have an apparently successful explanatory framework for the earlier stages: one in which genetic mutations hold ultimate causal and explanatory power. By contrast, on both empirical and conceptual grounds, it is not currently clear that mutations alone can explain the later stages of cancer. Can a different type of molecular change do better? Here, I introduce the “permissive binding theory” of cancer, which proposes that novel protein binding interactions are the key causal and explanatory entity in invasion and metastasis. It posits that binding is more abundant at baseline than we observe because it is restricted in normal physiology; that any large perturbation to physiological state revives this baseline abundance, unleashing many new binding interactions; and that a subset of these cause the cellular functions at the heart of oncogenesis, especially invasion and metastasis. Significant physiological perturbations occur in cancer cells in very early stages, and generally become more extreme with progression, providing interactions that continually fuel invasion and metastasis. The theory is compatible with, but not limited to, causal roles for the diverse molecular changes observed in cancer (e.g. gene expression or epigenetic changes), as these generally act causally upstream of proteins, and so may exert their effects by changing the protein binding interactions that occur in the cell. This admits the possibility that molecular changes that appear quite different may actually converge in creating the same few protein complexes, simplifying our picture of invasion and metastasis. If correct, the theory offers a concrete therapeutic strategy: targeting the key novel complexes. The theory is straightforwardly testable by large-scale identification of protein interactions in different cancers.