Scientists at Baylor College of Medicine report on studies in mice, which indicate that glioblastoma brain tumors impact on the activity of neighboring neurons, promoting a vicious cycle that alters gene expression and drives tumor-associated epilepsy and tumor progression. The findings, published in Nature, showed that variants of the PIK3CA gene promote tumor progression, and that two variants in particular altered the expression of genes involved in synaptic function. “Using a new functional genomics strategy, our research reveals a dynamic interplay between glioma cells and adjacent neurons,” said corresponding author Benjamin Deneen, PhD, professor of neurosurgery and in the Center for Stem Cell and Regenerative Medicine. “In this regard, glioma tumors exhibit Machiavellian behavior—glioma cells remodel the neuronal microenvironment toward hyperactivity, which in turn feeds back to the tumor, promoting its own growth.” Deneen and colleagues report on their studies in a paper titled, “PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis.”

The field of cancer genomics has linked many gene mutations and variants with cancer progression, and the wealth of data generated is being harnessed to develop approaches to personalized medicine that based on patient-specific genomic information. However, identifying which gene variants are truly causal and play a driving role in cancer progression, remains problematic. “One major obstacle in achieving this goal is decoding driver and passenger mutations from these cohorts …” the authors continued. “Whether related variants exert differential effects on both tumor and microenvironmental phenotypes remains unknown.”

The RTK–RAS–PI3K pathway has been shown to represent a key driver of tumorigenesis across all cancers, and 90% of glioblastoma tumours exhibit alterations in the pathway, the investigators continued. Studies indicate that mutations in the PI3K catalytic subunit PIK3CA are found in 11% of glioblastoma tumors. The researchers wanted to develop an experimental system that would let them identify new cancer genes in mouse models of brain tumors. To achieve this the Deneen lab collaborated with Baylor co-author Kenneth L Scott, PhD, to genetically engineer a mouse model of glioma into a novel, high-throughput screening platform. “To decode which of these PIK3CA variants function as drivers of glioblastoma, we established an in vivo complementation screening platform for glioblastoma.”

Using the platform, the researchers discovered several variants of PIK3CA that drive glioma development. Two of the PIK3CA variants, C420R and H1047R, stood out because they had the strongest effects. Interestingly, some of the genes specifically expressed in gliomas that carry the C420R and H1047R are involved in synapse formation, suggesting that the tumors may affect the synaptic balance of neighboring neurons.

Interestingly, tumors that carried either of the PIK3CA variants exhibited very different gene expression patterns. “Although C420R tumors demonstrated a notable increase in proliferative genes, we found two distinct patterns of synaptic gene dysregulation, with C420R tumors showing suppression of one subgroup of synaptic genes and H1047R tumors revealing robust upregulation of an entirely different set of synaptic genes,” the authors reported. “These findings demonstrate that similar variants can engender a diverse range of molecular properties in glioma tumors, reinforcing the importance of deciphering the selective functions of each driver variant …Together, these molecular analyses reveal that gliomas driven by different PIK3CA variants are endowed with distinct molecular features that can be uncoupled from PI3K activation (that is, C420R and H1047R).”

“These gene variants produce proteins that differ in only one amino acid—the building blocks of proteins—yet some of the variants generate tumors with molecular profiles that are quite different from the others,” noted Deneen, who also is a member of the Dan L Duncan Comprehensive Cancer Center and holds the Marian and Russell Blattner Chair at Baylor. “This was quite a surprise and tells us that seemingly similar PIK3CA variants promote glioma formation through very different mechanisms.”

To investigate these different mechanisms, Deneen and colleagues focused on the synaptic gene signatures, hypothesizing that alterations in synaptic gene expression could lead to seizures, network hyperexcitability and direct synaptic changes in their mouse model of glioma. To conduct these studies, Deneen partnered with co-author Jeffrey L. Noebels, MD, PhD, professor of neurology, neuroscience, and molecular and human genetics and Cullen Trust for Health Care Endowed Chair in Neurogenetics at Baylor.

Benjamin Deneen, PhD, is the corresponding author of this work. [Baylor College of Medicine]

“It is well established that synaptic imbalance can result in extensive changes in neuronal network connectivity and excitability, which in some cases culminates in seizure activity,” Deneen said. “Seizures are typical in glioma, but the underlying cellular and genetic mechanisms are not well understood. We took this finding as an opportunity to explore whether different PIK3CA variants can induce epilepsy in glioma and also to understand more about the mechanisms by which tumors promote neuronal hyperexcitability.”

Their studies showed that gliomas driven by C420R and H1047R variants do promote early onset of hyperexcitability in neurons surrounding the tumor and remodel synaptic networks by inducing synapse formation. Mice carrying these tumors had seizures that appeared much earlier than they did in mice bearing tumors driven by other PIK3CA variants.“ … variant-specific increases in hyperexcitability correlate with the relative changes in synaptic gene cohorts of C420R and H1047R tumors, which suggests that tumors driven by these variants result in early synaptic imbalance during the formative stages of tumor progression,” the team noted.

Further investigations into the mechanisms that mediate the effects of C420R and H1047R gliomas on their microenvironment, the researchers discovered that these gliomas selectively secreted several molecules of the glypican (GPC) family, and that one of these, GPC3, drove hyperexcitability and synaptic remodeling. Their results indicated that GPC3 itself can drive glioma formation, and showed that deleting GPC3 in C420R-driven mouse tumors resulted in longer survival times.

The studies provide the first evidence of a glioma-derived mechanism that manipulates the neuronal microenvironment during tumor progression. As the investigators concluded, “ … these findings further illustrate that crosstalk between glioma tumors and the surrounding neuronal microenvironment is a key contributor to malignant growth.”

“We have uncovered a central mechanism by which glioma cells alter neurons to establish environmental conditions in the brain that support growth,” Deenan stated. Therapeutically, we are actively examining how short circuiting glioma-to-neuron communication can be used to treat patients with these malicious brain tumors.”

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