Nature. The PIK3CA mutation promotes the formation of gliomas by increased neuronal excitability.

In the process of classifying the somatic mutation spectrum of all types of tumors, the rapid development of tumor genomics has led us to discover many types of mutations [1].these key advances are expected to usher in a new era of precision medicine.in precision therapy, the specific genomic information of patients is applied to clinical practice to guide the treatment.because not all mutations can affect malignant tumors, while other mutations perform specific functions in a specific environment, a major obstacle to achieving this goal is to screen out the key mutations in the driving genes.hotspot mutations represent the key mutations in the driving gene, which occur at a high frequency and can be found in different types of cancer.although this method is widely accepted, it ignores most other mutations and, crucially, these studies do not elucidate how cell function is affected by hot spot mutations.whether the related mutants have significant effects on tumor and microenvironment is still unknown.glioblastoma is a brain tumor with a high mortality rate. Glioblastoma exhibits a series of pathophysiological phenotypes, many of which are mediated by interactions with neuronal microenvironment.recent studies have shown that increased neuronal activity plays an important role in the proliferation and development of glioblastoma.it is still unclear whether there is interaction between glioblastomas and neurons, and how these tumors remodel the neuronal microenvironment to enhance activity is still unclear.on January 30, 2020, Benjamin deneen of Baylor Medical College published an article entitled PIK3CA variables selectively initiate brain activity during gliomagenes in nature.in this study, we developed a high-throughput screening platform in vivo using spontaneous mouse model of glioblastoma, and found several key mutants of PIK3CA.these mutants drive tumor formation by increasing glypican (GPC) secretion, changing tumor microenvironment, up regulating neuronal excitability and promoting proliferation.RTK – RAS – PI3K pathway is the key driving force for the occurrence of many kinds of tumors, and 90% of glioblastoma tumors will show the change of this pathway [2].sequencing of glioblastoma samples reveals some known hot spot mutations that drive multiple types of tumors.there were 63 other mutations in the coding region that were not classified.in order to understand which of these PIK3CA mutants act as the driving factors of glioblastoma, the authors established a screening platform for glioblastoma. the authors first selected a mouse glioblastoma model: 50% of the mice died of tumor one day after birth, relying on intrauterine electroporation (iue) and CRISPR – cas9 mediated NF1, Trp53 and PTEN knockout (called "3xcr"). the median survival of mice (called "2xcr") that removed PTEN induced RNA was prolonged. after the formation of glioma, the authors used a tumor specific DNA targeting sequence screening strategy in the 2xcr model as a substitute for the enrichment of mutants in tumors. the established PIK3CA hotspots (e545k and h1047r) and other mutants (r88q and c420r) that have not been found in glioma were enriched in the tumor. in order to confirm the specific function of these mutants, the authors expressed these mutants in 2xcr model respectively, and found that they can compensate for the deletion of PTEN knockout and promote tumor development, and they are similar to glioblastoma in pathological features. these data indicate that our method can identify identified hot spot mutations and new PIK3CA driven mutants in gliomas. among these mutations, c420r and h1047r mutants showed high PI3K activity and strong tumor driving force, while e545k r88q and m1043i mutants showed less activation. transcriptome sequencing showed that the expression of synaptic genes in one subgroup of c420r mutation was inhibited, while that of h1047r mutant was significantly up-regulated in another group. next, the authors used PDX model and EEG to evaluate nerve hyperactivity. It was found that h1047r mice showed early seizure of epilepsy, and the mutant promoted brain pleasure through cellular autonomic mechanism. however, c420r mice showed early onset of excitatory network, and this mutation promoted brain excitability through cellular non autonomous mechanism. using TCGA database analysis, we found that glypican 3 (GPC3) was highly expressed in high-grade glioblastoma. GPC3 is secreted by glial cells and promotes the growth and excitability of neurons [3]. the authors found that c420r mutation could drive the increase of GPC3 expression. experiments have shown that GPC3 can promote the occurrence and development of glioblastoma, manipulate the neuron microenvironment, thus accelerating neuronal overexcitation and seizures. this study has linked specific mutants to the phenotype of glioblastoma. PIK3CA mutant regulates tumor microenvironment through GPC3, promotes synaptic formation during early tumorigenesis, stimulates neuronal activity, and cooperates with neurons to coordinate hyperactivity and proliferation of neural network. original link: plate maker: Ke ref. 1. Chang, M. T. et al. Identifying recurrent mutations in cancer viruses widespan pread lineage diversity and mutation specificity. NAT. Biotechnology. 34, 155 – 163 (2016). 2. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004).3. Venkatesh, H. S. et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161, 803–816 (2015).