Expression of the Hippo Signaling Pathway in Glioblastoma Multiforme and Low-Grade Gliomas

Roarick Schollmeyer Author

03/27/2021 Added

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In an effort to identify novel targets for possibly treating Glioblastoma Multiforme (GBM), I investigate differential gene expression in the Hippo signaling pathway in GBM, low-grade gliomas, and normal samples. I conclude that genes responsible for activating the Hippo signaling pathway were generally expressed at lower levels in GBM compared to both low-grade gliomas and normal samples. In addition, genes responsible for inhibiting the Hippo signaling pathway were generally expressed at higher levels in GBM.

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[00:00:00.810]Hello,
[00:00:01.320]my name is Roarick Schollmeyer and I'll be talking about the expression of the hippo
[00:00:05.940]signaling pathway in glioblastoma multiforme and low grade gliomas.
[00:00:11.460]So glioblastoma multiforme or GBM for short is an incredibly
[00:00:16.050]deadly brain tumor with an average survival rate of about 15 months following
[00:00:20.550]diagnosis, it's very difficult to treat.
[00:00:24.060]And part of this is because GBM is able to spread into non-cancerous
[00:00:28.830]tissue and convert healthy cells into cancer cells.
[00:00:33.360]To my knowledge,
[00:00:34.050]the treatment of GBM consists of surgical resection followed by radiotherapy and
[00:00:38.790]cytotoxic drugs.
[00:00:40.770]But these treatments really have not improved patient outcomes since
[00:00:44.880]2005, at least not in a significant way.
[00:00:48.300]So therefore scientists looking to treat glioblastoma multiforme
[00:00:53.100]effectively may need to start looking into new areas of
[00:00:57.510]research.
[00:00:59.130]So while I was looking into the different variables that may aid GBMs ability to
[00:01:03.690]invade so successfully,
[00:01:05.190]I came across the role that stiffness may play healthy brain
[00:01:09.960]tissue can vary pretty greatly in the regional stiffness values.
[00:01:14.850]And they can be as low as 0.1 kilopascals to as high as 10
[00:01:19.140]kilopascals and as glioblastoma progresses,
[00:01:24.180]both the extracellular matrix and the tumor will begin to stiffen.
[00:01:28.890]And this is partly due to select secretions from GBM cells.
[00:01:33.510]Importantly,
[00:01:33.990]the stiffening of the extra cellular matrix allows for greater glial cell
[00:01:38.880]migration with rather inefficient migration potential in very soft
[00:01:43.770]tissue.
[00:01:44.820]It's also been found that yap is a mechanical sensor that senses mechanical
[00:01:48.900]forces such as increased environmental stiffness,
[00:01:52.350]and can respond by increasing the activation of yaps target genes,
[00:01:55.860]which have been shown to lead to the development of cancer through increasing
[00:02:00.690]cellular proliferation, organ growth,
[00:02:03.480]increased cell size and inhibiting apoptotic signals. With this in mind,
[00:02:08.160]I wanted to investigate how yap was regulated in gliomas and found that the
[00:02:12.990]hippo signaling pathway is a major regulator of YAP,
[00:02:18.090]this is a simplified schematic of hippo signaling that I made through bio
[00:02:22.170]render,
[00:02:22.680]which is also going to show the role of yap and Taz in nucleus in the
[00:02:27.600]red are the core hippo pathway kinases that are going to interact to eventually
[00:02:32.460]phosphorolate yap and Taz.
[00:02:34.530]And this phosphorolation not only prevents yap and Taz from entering the
[00:02:38.070]nucleus, but also tags them for proteasomal degradation.
[00:02:42.030]So basically if there's low hippo activation,
[00:02:44.640]then unphosphorylated yap and Taz are able to move into the nucleus and act as
[00:02:49.290]transcriptional.
[00:02:50.040]Coactivators primarily with tead family transcription factors to express
[00:02:54.900]many genes associated with cancer progression to build on the
[00:02:59.860]current understanding surrounding the role of mechano transduction. In gliomas,
[00:03:04.060]I examine changes in transcriptional levels of genes,
[00:03:07.000]controlling the hippo signaling pathway to do this.
[00:03:10.090]I use publicly available clinical data sets,
[00:03:13.780]from two different places to compare GBM gene expression to normal gene
[00:03:18.100]expression.
[00:03:18.640]I use the Rembrandt data set and to compare GBM gene expression to low
[00:03:23.500]grade glioma gene or gene expression.
[00:03:26.380]I use the TCGA pan-cancer Atlas project of 2018 data
[00:03:31.090]set analysis of gene expression was done through
[00:03:35.740]GraphPad prism while significance was assessed with nonparametric man with
[00:03:40.460]you tests. So what I found here was the,
[00:03:44.950]the hippo signaling pathway, um,
[00:03:48.340]was pretty easily broken down into two parts. And,
[00:03:52.120]this figure on the left is going to show the most well understood effectors of
[00:03:55.720]MST one and two kinases while MSD one and two are
[00:04:00.670]phosphorylated in complex with SAB one.
[00:04:03.160]This is going to lead to phosphorylation of lats one and two,
[00:04:06.850]and this is considered to be activation of the hippo pathway and figure two B
[00:04:11.100]I'm comparing normal to GBM expression of these genes and note
[00:04:15.940]that many of these genes have different names from their products.
[00:04:20.590]And these show a decrease in hippo signaling for the first half of the path.
[00:04:27.060]This figure shows, you know,
[00:04:30.000]a simplified schematic of the second half of this, uh, hippo signaling pathway,
[00:04:35.070]lots one and two can be phosphorylated by other MSC complex
[00:04:39.750]or, um, phosphorylated Bob one.
[00:04:42.600]And while I don't have enough time to go in depth on what each effector is
[00:04:46.080]doing,
[00:04:46.470]I can say that these data are consistent with a decrease in hippo signaling.
[00:04:52.110]Next,
[00:04:52.500]I compare hippo signaling between GBM
[00:04:57.690]samples and LGG samples.
[00:05:00.150]And this is because the world health organization grade two low grade gliomas
[00:05:04.230]almost always develop into high grade gliomas, such as GBM,
[00:05:08.790]as you see transcript levels of hippo activators,
[00:05:12.240]or almost all lower in GBM compared to LGG.
[00:05:16.530]And these results demonstrate the general decrease in action for the second half
[00:05:21.570]of the, or sorry,
[00:05:22.830]the first half of the signaling pathway when comparing GBM samples to
[00:05:27.360]LGG,
[00:05:29.550]this figure is comparing gene expression of the second half of the hippo pathway
[00:05:33.870]in GBM and LGG.
[00:05:36.030]What we see here is that many effectors that lead to yap degradation were
[00:05:39.720]significantly reduced in GBM compared to LGG to add to that
[00:05:44.520]yap and Taz transcript levels. Um,
[00:05:47.280]as well as aJuba an PP one which increased yap and Taz is abundance were
[00:05:52.230]significantly increased in GBM samples compared to LGG.
[00:05:57.440]Lastly,
[00:05:58.010]I wanted to analyze MRNs expression levels of 16 yap and Taz target
[00:06:02.780]genes whose dysregulation could have implications on GBM and LGG
[00:06:07.760]tumor Genesis.
[00:06:09.260]What I found was that nine yap and Taz transcriptional targets were expressed
[00:06:14.120]significantly higher in GBM samples compared to normal samples.
[00:06:19.040]Furthermore, expression of 11,
[00:06:20.810]yap and Taz transcriptional targets were significantly higher in GBM samples
[00:06:25.250]compared to LGG samples,
[00:06:27.410]and really collectively these results reinforce the notion of decrease hippo
[00:06:32.150]signaling followed by an increase in yap and Taz action in the
[00:06:36.710]nucleus of GBM cells.
[00:06:39.980]So this figure I'm using more so to help summarize my findings
[00:06:44.810]also made on bio render. Um, genes are kind of separated based on their role.
[00:06:49.640]And what we see here is that M RNA expression of the majority of genes
[00:06:53.000]responsible for activating the hippo signaling pathway is decreased in
[00:06:57.770]GBM patients compared to both normal and LGG patients,
[00:07:01.880]lower hippo activation leads to higher abundance of yap and Taz,
[00:07:05.510]which implies a pathogenic role for these two transcriptional coactivators
[00:07:10.490]and gliomas consistent with this genes that are responsible for inhibiting
[00:07:15.230]core hippo kinases mostly seemed to show higher expression in
[00:07:19.730]GBM compared to LGG in normal samples.
[00:07:23.300]It was found that there are elevated expression levels of many yap and
[00:07:28.250]Taz transcriptional targets in GBM compared to LGG and
[00:07:32.840]normal samples. To wrap this up,
[00:07:35.900]it seems that the pairing of yap and Taz to teach transcription factors does
[00:07:40.760]play an important role in glioma metastasis.
[00:07:44.870]So finding a way to decrease or mediate stiffness in the environment may have
[00:07:49.100]favorable effects in both limiting GBM migration potential and
[00:07:53.810]through decreased action. Next, a possible therapy for GBM,
[00:07:58.730]maybe through the inhibition of yap and Taz.
[00:08:02.000]They're actually a few clinically approved drugs that indirectly inhibit
[00:08:06.740]yap and taz.
[00:08:07.520]So perhaps deliberate repurposing of the most promising yap and Taz
[00:08:11.990]inhibitors may inhibit glioma metastasis and improve patient
[00:08:16.970]prognosis. Lastly,
[00:08:18.830]I think that an interesting future direction for this research would be to look
[00:08:22.610]into analyzing hippo signaling expression levels between LGG and
[00:08:27.560]normal samples. And that concludes my presentation. I would like to thank Dr.
[00:08:32.180]Kidambi and Dr. Khalimonchuk for taking the time to advise me.

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Expression of the Hippo Signaling Pathway in Glioblastoma Multiforme and Low-Grade Gliomas

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