Cell Reports,
Journal Year:
2023,
Volume and Issue:
42(1), P. 112016 - 112016
Published: Jan. 1, 2023
Tumors
with
mutations
in
chromatin
regulators
present
attractive
targets
for
DNA
hypomethylating
agent
5-aza-2′-deoxycytidine
(DAC)
therapy,
which
further
disrupts
cancer
cells'
epigenomic
fidelity
and
reactivates
transposable
element
(TE)
expression
to
drive
viral
mimicry
responses.
SETD2
encodes
a
histone
methyltransferase
(H3K36me3)
is
prevalently
mutated
advanced
kidney
cancers.
Here,
we
show
that
SETD2-mutant
cells
are
especially
sensitive
vitro
vivo
DAC
treatment.
We
find
the
response
direct
consequences
of
mis-splicing
events,
such
as
exon
inclusions
or
extensions,
triggered
by
treatment
an
SETD2-loss
context.
Comprehensive
analysis
reveals
H3K9me3
deposition,
rather
than
methylation
dynamics,
across
intronic
TEs
might
contribute
elevated
rates.
Through
transcriptomic
analyses,
SETD2-deficient
cancers
prone
mis-splicing,
can
be
therapeutically
exacerbated
increase
activation
provide
synergy
combinatorial
immunotherapy
approaches.
Cell,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Feb. 1, 2025
Clear
cell
renal
carcinoma
(ccRCC),
despite
having
a
low
mutational
burden,
is
considered
immunogenic
because
it
occasionally
undergoes
spontaneous
regressions
and
often
responds
to
immunotherapies.
The
signature
lesion
in
ccRCC
inactivation
of
the
VHL
tumor
suppressor
gene
consequent
upregulation
HIF
transcription
factor.
An
earlier
case
report
described
patient
who
was
cured
by
an
allogeneic
stem
transplant
later
found
have
donor-derived
T
cells
that
recognized
ccRCC-specific
peptide
encoded
HIF-responsive
endogenous
retrovirus
(ERV),
ERVE-4.
We
ERVE-4
one
many
ERVs
are
induced
HIF,
translated
into
HLA-bound
peptides
ccRCCs,
capable
generating
antigen-specific
responses.
Moreover,
ERV
expression
can
be
non-ccRCC
tumors
with
clinical-grade
stabilizers.
These
findings
implications
for
leveraging
cancer
immunotherapy.
Nature Communications,
Journal Year:
2023,
Volume and Issue:
14(1)
Published: Feb. 21, 2023
Inter-cellular
movement
of
"prion-like"
proteins
is
thought
to
explain
propagation
neurodegeneration
between
cells.
For
example,
abnormally
phosphorylated
cytoplasmic
inclusions
TAR-DNA-Binding
protein
(TDP-43)
proposed
underlie
progression
amyotrophic
lateral
sclerosis
(ALS)
and
frontotemporal
dementia
(FTD).
But
unlike
transmissible
prion
diseases,
ALS
FTD
are
not
infectious
injection
aggregated
TDP-43
sufficient
cause
disease.
This
suggests
a
missing
component
positive
feedback
necessary
sustain
disease
progression.
We
demonstrate
that
endogenous
retrovirus
(ERV)
expression
proteinopathy
mutually
reinforcing.
Expression
either
Drosophila
mdg4-ERV
(gypsy)
or
the
human
ERV,
HERV-K
(HML-2)
each
stimulate
aggregation
TDP-43.
Viral
ERV
transmission
also
triggers
pathology
in
recipient
cells
express
physiological
levels
TDP-43,
whether
they
contact
at
distance.
mechanism
potentially
underlies
proteinopathy-caused
neurodegenerative
through
neuronal
tissue.
Cancer Research Communications,
Journal Year:
2024,
Volume and Issue:
4(4), P. 986 - 1003
Published: March 26, 2024
Abstract
Detection
of
viral
double-stranded
RNA
(dsRNA)
is
an
important
component
innate
immunity.
However,
many
endogenous
RNAs
containing
regions
can
be
misrecognized
and
activate
The
IFN-inducible
ADAR1-p150
suppresses
dsRNA
sensing,
essential
function
for
adenosine
deaminase
acting
on
1
(ADAR1)
in
cancers,
including
breast.
Although
has
been
well
established
this
role,
the
functions
constitutively
expressed
ADAR1-p110
isoform
are
less
understood.
We
used
proximity
labeling
to
identify
putative
ADAR1-p110–interacting
proteins
breast
cancer
cell
lines.
Of
identified,
helicase
DHX9
was
particular
interest.
Knockdown
ADAR1-dependent
lines
caused
death
activation
sensor
PKR.
In
ADAR1-independent
lines,
combined
knockdown
ADAR1,
but
neither
alone,
multiple
sensing
pathways
leading
a
mimicry
phenotype.
Together,
these
results
reveal
role
suppressing
by
pathways.
Significance:
These
findings
implicate
as
suppressor
sensing.
some
loss
alone
sufficient
cause
pathways,
while
other
redundantly
with
ADAR1
suppress
pathway
activation.
Science Advances,
Journal Year:
2024,
Volume and Issue:
10(13)
Published: March 27, 2024
While
pancreatic
ductal
adenocarcinomas
(PDACs)
are
addicted
to
KRAS-activating
mutations,
inhibitors
of
downstream
KRAS
effectors,
such
as
the
MEK1/2
kinase
inhibitor
trametinib,
devoid
therapeutic
effects.
However,
extensive
rewiring
regulatory
circuits
driven
by
attenuation
pathway
may
induce
vulnerabilities
relevance.
An
in-depth
molecular
analysis
transcriptional
and
epigenomic
alterations
occurring
in
PDAC
cells
initial
hours
after
inhibition
trametinib
unveiled
induction
endogenous
retroviruses
(ERVs)
escaping
epigenetic
silencing,
leading
production
double-stranded
RNAs
increased
expression
interferon
(IFN)
genes.
We
tracked
ERV
activation
early
transcription
factor
ELF3,
which
extensively
bound
activated
nonsilenced
retroelements
synergized
with
IRF1
(interferon
1)
IFNs
IFN-stimulated
Trametinib-induced
viral
mimicry
be
exploited
rational
design
combination
therapies
immuno-oncology.
Science Advances,
Journal Year:
2024,
Volume and Issue:
10(29)
Published: July 17, 2024
Cancer
cells
exhibit
rewired
transcriptional
regulatory
networks
that
promote
tumor
growth
and
survival.
However,
the
mechanisms
underlying
formation
of
these
pathological
remain
poorly
understood.
Through
a
pan-cancer
epigenomic
analysis,
we
found
primate-specific
endogenous
retroviruses
(ERVs)
are
rich
source
enhancers
displaying
cancer-specific
activity.
In
colorectal
cancer
other
epithelial
tumors,
oncogenic
MAPK/AP1
signaling
drives
activation
derived
from
ERV
family
LTR10.
Functional
studies
in
revealed
LTR10
elements
regulate
tumor-specific
expression
multiple
genes
associated
with
tumorigenesis,
such
as
ATG12
XRCC4
.
Within
human
population,
individual
germline
somatic
structural
variation
resulting
highly
mutable
internal
tandem
repeat
region,
which
affects
AP1
binding
Our
findings
reveal
ERV-derived
contribute
to
dysregulation
response
shape
evolution
networks.
