Neurodevelopmental disorders, like cancer, are connected to impaired chromatin remodelers, PI3K/mTOR, and PAK1-regulated MAPK

Abstract

Neurodevelopmental disorders (NDDs) and cancer share proteins, pathways, and mutations. Their clinical symptoms are different. However, individuals with NDDs have higher probabilities of eventually developing cancer. Here, we review the literature and ask how the shared features can lead to different medical conditions and why having an NDD first can increase the chances of malignancy. To explore these vital questions, we focus on dysregulated PI3K/mTOR, a major brain cell growth pathway in differentiation, and MAPK, a critical pathway in proliferation, a hallmark of cancer. Differentiation is governed by chromatin organization, making aberrant chromatin remodelers highly likely agents in NDDs. Dysregulated chromatin organization and accessibility influence the lineage of specific cell brain types at specific embryonic development stages. PAK1, with pivotal roles in brain development and in cancer, also regulates MAPK. We review, clarify, and connect dysregulated pathways with dysregulated proliferation and differentiation in cancer and NDDs and highlight PAK1 role in brain development and MAPK regulation. Exactly how PAK1 activation controls brain development, and why specific chromatin remodeler components, e.g., BAF170 encoded by SMARCC2 in autism, await clarification.

Neurodevelopmental disorders and cancer networks share pathways; but differ in mechanisms, signaling strength, and outcome

“…Expression profiles of differentiation and proliferation appear moderate in ASD, which suggests weak signal activation in cell proliferation (Nussinov et al, 2023). However, the suppression of differentiation and the overexpression of proliferation indicate strong activation of the proliferation state in cancer.…”

“…We extracted the graphlet motifs, small significant subnetworks, from the reference interactome HIPPIE through mutations with an unsupervised learning approach (Alanis-Lobato et al, 2017;Milenković and Pržulj, 2008). To select the most relevant interactions in a disease from the graphlet motifs with the PageRankFlux algorithm, we constructed the ASD-specific network with 350 proteins and 1291 interactions, and the breast cancer-specific network with 284 proteins and 1878 interactions (Supplementary Data 1) (Figure 4A) (Arici and Tuncbag, 2023;Rubel and Ritz, 2020). As can be expected based on our relatively weak mutation outcome premise of NDDs, some critical TFs such as Myc, p53, and Jun with cancer driver mutations are not frequently mutated in ASD.…”

“…Each interaction in HIPPIE was scored with a confidence score that was computationally optimized and weighted by the amount and quality of the experimental evidence of PPI. The network inference tool, pyPARAGON (PAgeRAnkflux on Graphlet-guided-network for multi-Omic data integratioN), inferred ASD and breast cancer-specific networks by scoring interactions with PageRank Flux and identifying validated graphlet motifs, the union of which constructs a graphlet-guided network (GGN) (Arici and Tuncbag, 2023). The PageRank algorithm weighted all nodes in a reference network.…”

“…They may originate from dysregulation of neuron differentiation, during synapse formation and maturation, or other complex processes in the course of brain evolution, such as emergence from progenitor cells, neuron phenotypic specification, migration, and specific synaptic contacts. Flaws can result in faulty wired neuronal circuits (Nussinov et al, 2023(Nussinov et al, , 2022a. Despite differing from processes associated with the emergence of cancer, data indicate that NDDs and cancer are related, with immunity likely the common factor.…”

“…This further suggests that in addition to nodes in the major signaling pathways, transcription factors (TFs) and chromatin remodelers, which govern chromatin organization, are agents in NDDs. Gene accessibility influences the lineage of specific brain cell types at specific embryonic development stages (Nussinov et al, 2023).…”