PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis

Yu, Kwanha; Lin, Chih-Hsu; Hatcher, Asante; Lozzi, Brittney; Kong, Kathleen; Huang-Hobbs, Emmet; Cheng, Yi Ting; Beechar, Vivek B.; Zhu, Wenyi; Zhang, Yiqun; Chen, Ken; Mills, Gordon B.; Mohila, Carrie A.; Creighton, Chad J.; Noebels, Jeffrey L.; Scott, Kenneth L.; Deneen, Benjamin

doi:10.1038/s41586-020-1952-2

Cited by 142 publications

(138 citation statements)

References 39 publications

Supporting

Mentioning

128

Contrasting

Order By: Relevance

“…It remains unclear whether the tumor microenvironment of the exceptional responders is dictated by the intrinsic genetic/epigenetic landscape of the tumor, patient-specific genetics/physiology, or a combination of the two. Recent findings that distinct PIK3CA mutations induce tumor microenvironment with differential capacity for synapse formation suggest the primacy of tumor genetics in shaping its microenvironment (77). Applied to our findings, this model would suggest that microglia/macrophage recruitment is driven by mutations within the cancer genome through cell-autonomous mechanisms.…”

Section: Discussionsupporting

confidence: 58%

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

Kaneda²,

et al. 2020

Preprint

View full text Add to dashboard Cite

Precision medicine in oncology leverages clinical observations of exceptional response.Towards an understanding of the molecular features that define this response, we applied an integrated, multi-platform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted isoform of PI3K, PI3Kg, by pharmacologic inhibition or genetic inactivation, disrupted this signaling axis by suppressing microglia/macrophage accumulation and associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kg inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kg in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kg inhibition as a glioblastoma therapy. 3 Significance StatementUnderstanding the basis for exceptional responders represents a key pillar in the framework of precision medicine. In this study, we utilized distinct informatics platforms to analyze the expression profiles of clinically annotated tumor specimens derived from patients afflicted with glioblastoma, the most common form of primary brain cancer. These analyses converged on prognostic contributions from glioblastoma-associated microglia/macrophages. Glioblastoma-associated microglia secreted interleukin 11 (IL11) to activate a STAT3-MYC signaling axis in glioblastoma cells, facilitating resistance to the standard-of-care chemotherapy, temozolomide. Microglia recruitment and IL11 secretion were dependent on the myeloid specific phosphoinositide-3-kinase gamma isoform (PI3Kg). Inhibition or genetic inactivation of PI3Kg in murine glioblastoma models recapitulated expression profiles observed in specimens derived from exceptional responders, suggesting potential for clinical translation.

show abstract

Section: Discussionsupporting

confidence: 58%

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

Kaneda²,

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The high vulnerability of fast-spiking interneurons to glioma-induced excitotoxicity in the tumor-adjacent zone (Tewari et al, 2018) may trigger a vicious cycle with reduced GABA release, increased firing of pyramidal neurons, and consequently enhanced tumor growth. A similar scenario is indicated by the recent work of Deneen and collaborators (Yu et al, 2020), where specific mutations harboured by transplanted glioma cells render tumours more aggressive and lethal. Gliomas driven by these variants shape synaptic connectivity in the peritumoral region, with enhanced density of excitatory boutons and decreased inhibitory synapses, and consequently heightened network hyperexcitability.…”

Section: Optogenetic Stimulation Of Principal Cells and Fast-spiking supporting

confidence: 66%

“…Infiltrating glioma cells also perturb chloride homeostasis in pyramidal neurons, with dowregulation of KCC2 (K-Cl cotransporter 2) expression and consequent excitatory actions of gamma-aminobutyric acid (GABA) (Campbell et al, 2015;Conti et al, 2011;Pallud et al, 2014). Glioma cells harbouring specific genetic mutations drive synaptic changes in the surrounding neuronal microenvironment, specifically an enhancement in the density of excitatory boutons coupled with a decrease in inhibitory puncta (Yu et al, 2020). Altogether, these alterations render peritumoral neuronal networks hyper-excitable and more prone to seizures (Buckingham et al, 2011;Venkatesh et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Differential roles of pyramidal and fast-spiking, GABAergic neurons in the control of glioma cell proliferation

Tantillo

Vannini

Cerri

et al. 2020

Preprint

View full text Add to dashboard Cite

AbstractRecent studies have demonstrated an active role for neurons in glioma progression. Specifically, peritumoral neurons establish functional excitatory synapses with glioma cells, and optogenetic stimulation of cortical pyramidal neurons drives tumor progression. However, the specific role of different subsets of cortical neurons, such as GABAergic interneurons, remains unexplored. Here, we directly compared the effects of optogenetic stimulation of pyramidal cells vs. fast-spiking, GABAergic neurons. In mice inoculated with GL261 cells into the motor cortex, we show that optogenetic stimulation of pyramidal neurons enhances glioma cell proliferation. In contrast, optogenetic stimulation of fast-spiking, parvalbumin-positive interneurons reduces proliferation as measured by BrdU incorporation and Ki67 immunolabelling. Since both principal cells and fast-spiking interneurons are directly activated by sensory afferent input, we next placed tumors in the occipital cortex to test the impact of visual stimulation/deprivation. We report that total lack of visual input via dark rearing enhances the density of proliferating glioma cells, while daily visual stimulation by gratings of different spatial frequencies and contrast reduces tumor growth. The effects of sensory input are region-specific, as visual deprivation has no significant effect on tumor proliferation in mice with gliomas in the motor cortex. We also report that sensory stimulation combined with temozolomide administration delays the loss of visual responses in peritumoral neurons. Altogether, these data demonstrate complex effects of different neuronal subtypes in the control of glioma proliferation.HighlightsActivity of GABAergic neurons reduces glioma cell proliferationLevels of sensory afferent input regulate tumor proliferationEffects of sensory input are region-specific

show abstract

“…GPCs are known to be expressed in several cancers and gained attention as possible biomarkers for various cancer progression. At present, the roles for GPC1 and GPC3 in controlling the proliferation of glioma cells have been reported; the overexpression of GPC1 in U87 glioma cells enhanced FGF-2stimulated proliferation of cells through enhancing FGF-2 signaling [18], whereas knockdown of GPC1 in U251 glioma cells reduced the cellular growth and proliferation [19]; GPC3 drived gliomagenesis and initiated the brain hyperexcitability [43]. In fact, the expression of GPC1 and GPC3 appears to be highly tissue speci c. Of six GPCs, GPC1 is abundantly expressed in brain [44].…”

Section: Discussionmentioning

confidence: 99%

“…In fact, the expression of GPC1 and GPC3 appears to be highly tissue speci c. Of six GPCs, GPC1 is abundantly expressed in brain [44]. Although the expression of GPC3 protein have recently been detected in human glioma tissues by immunohistochemistry [43], Pilia previously reported that GPC3 mRNA is not detectable expressed in brain [45]. In view of the fact that GPC1 is more abundantly expressed in brain, we focus our study on GPC1 and demonstrated that the proliferation capability of U118 glioma cells was promoted by overexpressed GPC1 while weakened by deleted GPC1.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of Annexin A2 Promotes Proliferation by Forming a Glypican 1 / c-Myc Positive Feedback Loop: Prognostic Significance in Human Glioma

Nie

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Glioma, with varying malignancy grades, is the most common primary brain tumor. It is urgent to set up a reliable prediction system for the tumor grade and prognosis in glioma patients. We aimed to clarify the complicated crosstalk of Annexin A2 (ANXA2) with Glypican 1 (GPC1) and demonstrate whether combined indexes of ANXA2 and GPC1 could improve the prognostic evaluation for glioma patients.Methods: The role of ANXA2 and GPC1 in proliferation and their relationship were validated in glioma cells. 164 glioma samples were analyzed for association between co-expression of ANXA2 and GPC1 and patient clinicopathological features and prognosis. Results: We found that ANXA2 induced glioma cellular proliferation in a c-Myc-dependent manner. ANXA2 increased the expression of GPC1 via c-Myc and the upregulated GPC1 further promoted the c-Myc level forming a positive feedback loop, which eventually led to enhanced proliferation of glioma cells. Both quantitative reverse transcription-polymerase chain reaction (qRT-RCR) and immunohistochemistry revealed that ANXA2 was upregulated in glioma tissues and coincided with the overexpression of GPC1. Glioma patients with high both ANXA2 and GPC1 tended to have higher rate of tumor recurrence and shorter overall survival (OS). Multivariate analyses revealed that the combination of ANXA2 and GPC1 was an independent prognostic indicator for time to recurrence and OS. Conclusions: The overexpression of ANXA2 promotes proliferation by forming a GPC1/c-Myc positive feedback loop, and ANXA2 and its downstream target GPC1 could be a potential “combination biomarker” for predicting prognosis of glioma.

show abstract

PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis

Cited by 142 publications

References 39 publications

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

Differential roles of pyramidal and fast-spiking, GABAergic neurons in the control of glioma cell proliferation

Overexpression of Annexin A2 Promotes Proliferation by Forming a Glypican 1 / c-Myc Positive Feedback Loop: Prognostic Significance in Human Glioma

Contact Info

Product

Resources

About