Expression of the Hippo Signaling Pathway in Glioblastoma Multiforme and Low-Grade Gliomas
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.
icon search Searchable Transcript
Toggle between list and paragraph view.
[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
[00:00:40.770]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
[00:00:59.130]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
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.
[00:01:33.990]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
[00:01:44.820]It's also been found that yap is a
mechanical sensor that senses mechanical
[00:01:48.900]forces such as increased
[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
[00:02:22.680]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
[00:02:50.040]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
[00:03:18.640]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
[00:04:46.470]I can say that these data are consistent
with a decrease in hippo signaling.
[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
[00:05:29.550]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.
[00:05:58.010]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
[00:06:09.260]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
[00:08:18.830]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.
Log in to post comments