Hello,
my name is Roarick Schollmeyer and I'll be talking about the expression of the hippo
signaling pathway in glioblastoma multiforme and low grade gliomas.
So glioblastoma multiforme or GBM for short is an incredibly
deadly brain tumor with an average survival rate of about 15 months following
diagnosis, it's very difficult to treat.
And part of this is because GBM is able to spread into non-cancerous
tissue and convert healthy cells into cancer cells.
To my knowledge,
the treatment of GBM consists of surgical resection followed by radiotherapy and
cytotoxic drugs.
But these treatments really have not improved patient outcomes since
2005, at least not in a significant way.
So therefore scientists looking to treat glioblastoma multiforme
effectively may need to start looking into new areas of
research.
So while I was looking into the different variables that may aid GBMs ability to
invade so successfully,
I came across the role that stiffness may play healthy brain
tissue can vary pretty greatly in the regional stiffness values.
And they can be as low as 0.1 kilopascals to as high as 10
kilopascals and as glioblastoma progresses,
both the extracellular matrix and the tumor will begin to stiffen.
And this is partly due to select secretions from GBM cells.
Importantly,
the stiffening of the extra cellular matrix allows for greater glial cell
migration with rather inefficient migration potential in very soft
tissue.
It's also been found that yap is a mechanical sensor that senses mechanical
forces such as increased environmental stiffness,
and can respond by increasing the activation of yaps target genes,
which have been shown to lead to the development of cancer through increasing
cellular proliferation, organ growth,
increased cell size and inhibiting apoptotic signals. With this in mind,
I wanted to investigate how yap was regulated in gliomas and found that the
hippo signaling pathway is a major regulator of YAP,
this is a simplified schematic of hippo signaling that I made through bio
render,
which is also going to show the role of yap and Taz in nucleus in the
red are the core hippo pathway kinases that are going to interact to eventually
phosphorolate yap and Taz.
And this phosphorolation not only prevents yap and Taz from entering the
nucleus, but also tags them for proteasomal degradation.
So basically if there's low hippo activation,
then unphosphorylated yap and Taz are able to move into the nucleus and act as
transcriptional.
Coactivators primarily with tead family transcription factors to express
many genes associated with cancer progression to build on the
current understanding surrounding the role of mechano transduction. In gliomas,
I examine changes in transcriptional levels of genes,
controlling the hippo signaling pathway to do this.
I use publicly available clinical data sets,
from two different places to compare GBM gene expression to normal gene
expression.
I use the Rembrandt data set and to compare GBM gene expression to low
grade glioma gene or gene expression.
I use the TCGA pan-cancer Atlas project of 2018 data
set analysis of gene expression was done through
GraphPad prism while significance was assessed with nonparametric man with
you tests. So what I found here was the,
the hippo signaling pathway, um,
was pretty easily broken down into two parts. And,
this figure on the left is going to show the most well understood effectors of
MST one and two kinases while MSD one and two are
phosphorylated in complex with SAB one.
This is going to lead to phosphorylation of lats one and two,
and this is considered to be activation of the hippo pathway and figure two B
I'm comparing normal to GBM expression of these genes and note
that many of these genes have different names from their products.
And these show a decrease in hippo signaling for the first half of the path.
This figure shows, you know,
a simplified schematic of the second half of this, uh, hippo signaling pathway,
lots one and two can be phosphorylated by other MSC complex
or, um, phosphorylated Bob one.
And while I don't have enough time to go in depth on what each effector is
doing,
I can say that these data are consistent with a decrease in hippo signaling.
Next,
I compare hippo signaling between GBM
samples and LGG samples.
And this is because the world health organization grade two low grade gliomas
almost always develop into high grade gliomas, such as GBM,
as you see transcript levels of hippo activators,
or almost all lower in GBM compared to LGG.
And these results demonstrate the general decrease in action for the second half
of the, or sorry,
the first half of the signaling pathway when comparing GBM samples to
LGG,
this figure is comparing gene expression of the second half of the hippo pathway
in GBM and LGG.
What we see here is that many effectors that lead to yap degradation were
significantly reduced in GBM compared to LGG to add to that
yap and Taz transcript levels. Um,
as well as aJuba an PP one which increased yap and Taz is abundance were
significantly increased in GBM samples compared to LGG.
Lastly,
I wanted to analyze MRNs expression levels of 16 yap and Taz target
genes whose dysregulation could have implications on GBM and LGG
tumor Genesis.
What I found was that nine yap and Taz transcriptional targets were expressed
significantly higher in GBM samples compared to normal samples.
Furthermore, expression of 11,
yap and Taz transcriptional targets were significantly higher in GBM samples
compared to LGG samples,
and really collectively these results reinforce the notion of decrease hippo
signaling followed by an increase in yap and Taz action in the
nucleus of GBM cells.
So this figure I'm using more so to help summarize my findings
also made on bio render. Um, genes are kind of separated based on their role.
And what we see here is that M RNA expression of the majority of genes
responsible for activating the hippo signaling pathway is decreased in
GBM patients compared to both normal and LGG patients,
lower hippo activation leads to higher abundance of yap and Taz,
which implies a pathogenic role for these two transcriptional coactivators
and gliomas consistent with this genes that are responsible for inhibiting
core hippo kinases mostly seemed to show higher expression in
GBM compared to LGG in normal samples.
It was found that there are elevated expression levels of many yap and
Taz transcriptional targets in GBM compared to LGG and
normal samples. To wrap this up,
it seems that the pairing of yap and Taz to teach transcription factors does
play an important role in glioma metastasis.
So finding a way to decrease or mediate stiffness in the environment may have
favorable effects in both limiting GBM migration potential and
through decreased action. Next, a possible therapy for GBM,
maybe through the inhibition of yap and Taz.
They're actually a few clinically approved drugs that indirectly inhibit
yap and taz.
So perhaps deliberate repurposing of the most promising yap and Taz
inhibitors may inhibit glioma metastasis and improve patient
prognosis. Lastly,
I think that an interesting future direction for this research would be to look
into analyzing hippo signaling expression levels between LGG and
normal samples. And that concludes my presentation. I would like to thank Dr.
Kidambi and Dr. Khalimonchuk for taking the time to advise me.