Biomolecular Recognition and Binding Mechanisms

Division Of Basic Sciences - Nci

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Abstract

Early clues to tumors and their microenvironments come from embryonic development. Here we review the literature and consider whether the embryonic brain and its pathologies can serve as a better model. Among embryonic organs, the brain is the most heterogenous and complex, with multiple lineages leading to wide spectrum of cell states and types. Its dysregulation promotes neurodevelopmental brain pathologies and pediatric tumors. Embryonic brain pathologies point to the crucial importance of spatial heterogeneity over time, akin to the tumor microenvironment. Tumors dedifferentiate through genetic mutations and epigenetic modulations; embryonic brains differentiate through epigenetic modulations. Our innovative review proposes learning developmental brain pathologies to target tumor evolution-and vice versa. We describe ways through which tumor pharmacology can learn from embryonic brains and their pathologies, and how learning tumor, and its microenvironment, can benefit targeting neurodevelopmental pathologies. Examples include pediatric low-grade versus high-grade brain tumors as in rhabdomyosarcomas and gliomas. Aggressive tumors pose ultra-challenges to drug resistance. Anti-cancer treatments are often unsuccessful, and single-cell technologies to rein drug resistance mechanisms are still fruitless. The National Cancer Institute defines aggressive cancers at the tissue level, describing them as those that spread rapidly, despite severe treatment. At the molecular, foundational level, the quantitative biophysics discipline defines aggressive cancers as harboring a large number of (overexpressed, or mutated) crucial signaling proteins in major proliferation pathways populating their active conformations, primed for their signal transduction roles. This comprehensive review explores highly aggressive cancers on the foundational and cell signaling levels, focusing on the differences between highly aggressive cancers and the more treatable ones. It showcases aggressive tumors as harboring massive, cancer-promoting, catalysis-primed oncogenic proteins, especially through certain overexpression scenarios, as predisposed aggressive tumor candidates. Our examples narrate strong activation of ERK1/2, and other oncogenic proteins, through malfunctioning chromatin and crosslinked signaling, and how they activate multiple proliferation pathways. They show the increased cancer heterogeneity, plasticity, and drug resistance. Our review formulates the principles underlying cancer aggressiveness on the molecular level, discusses scenarios, and describes drug regimen (single drugs and drug combinations) for PDAC, NSCLC, CRC, HCC, breast and prostate cancers, glioblastoma, neuroblastoma, and leukemia as examples. All show overexpression scenarios of master transcription factors, transcription factors with gene fusions, copy number alterations, dysregulation of the epigenetic codes and epithelial-to-mesenchymal transitions in aggressive tumors, as well as high mutation loads of vital upstream signaling regulators, such as EGFR, c-MET, and K-Ras, befitting these principles. Small GTPases Ras, Rac, and RhoA are crucial regulators of cellular functions. They also act in dysregulated cell proliferation and transformation. Multiple publications have focused on illuminating their roles and mechanisms, including in immune system pathologies. Their functions in neurology-related diseases, neurodegeneration and neurodevelopment, are also emerging, as well as their potential as pharmacological targets in both pathologies. Observations increasingly suggest that these pathologies may relate to activation (or suppression) of signaling by members of the Ras superfamily, especially Ras, Rho, and Rac isoforms, and components of their signaling pathways. Germline (or embryonic) mutations that they harbor are responsible for neurodevelopmental disorders, such as RASopathies, autism spectrum disorder, and dilated cardiomyopathy. In aging, they promote neurodegenerative diseases, with Rho GTPase featuring in their pharmacology, as in the case of Alzheimer's disease (AD). Significantly, drugs with observed anti-AD activity, particularly those involved in cardiovascular systems, are associated with the RhoA signaling, as well as cerebral vasculature in brain development and aging. This leads us to suggest that anti-AD drugs could inform neurodevelopmental disorders, including pediatric low-grade gliomas pharmacology. Neurodevelopmental disorders associated with RhoA, like autism, are also connected with vascular systems, thus could be targets of vascular system-connected drugs.