Although
the
age
of
genome
gave
us
much
insight
about
how
our
organs
fail
with
disease,
it
also
suggested
that
diseases
do
not
arise
from
mutations
alone;
rather,
they
develop
as
we
age.
In
this
Review,
examine
wound
healing
might
act
to
ignite
disease.
Wound
works
well
when
are
younger,
repairing
damage
accidents,
environmental
assaults,
and
battles
pathogens.
Yet,
accumulation
tissue
damage,
repair
process
can
devolve,
leading
inflammation,
fibrosis,
neoplastic
signaling.
We
discuss
healthy
responses
bodies
misappropriate
these
pathways
in
focus
predominantly
on
epithelial-based
(lung
skin)
diseases,
similar
operate
cardiac,
muscle,
neuronal
diseases.
Objective
The
optimal
therapeutic
response
in
cancer
patients
is
highly
dependent
upon
the
differentiation
state
of
their
tumours.
Pancreatic
ductal
adenocarcinoma
(PDA)
a
lethal
that
harbours
distinct
phenotypic
subtypes
with
preferential
sensitivities
to
standard
therapies.
This
study
aimed
investigate
intratumour
heterogeneity
and
plasticity
cell
states
PDA
order
reveal
state-specific
regulators.
Design
We
analysed
single-cell
expression
profiling
mouse
PDAs,
revealing
identified
pathways
activated
different
states.
performed
comparative
analysis
murine
human
confirmed
diversity
specimens
by
immunolabeling.
assessed
function
regulators
using
models
PDA,
organoids,
lines
orthotopically
grafted
tumour
models.
Results
Our
immunolabeling
show
mucus
production
programme
regulated
transcription
factor
SPDEF
active
precancerous
lesions
classical
subtype
—
most
common
state.
maintains
supports
transformation
vivo
.
tumour-promoting
mediated
its
target
genes
AGR2
ERN2
/IRE1β
regulate
production,
inactivation
impairs
growth
facilitates
interconversion
from
towards
basal-like
differentiation.
Conclusions
findings
expand
our
understanding
transcriptional
programmes
PDAs
differentiation,
determine
as
specific
vulnerabilities
these
phenotype
switching
mechanism
determinants.
Cancer Discovery,
Год журнала:
2024,
Номер
14(10), С. 1964 - 1989
Опубликована: Июль 3, 2024
Abstract
Pancreatic
cancer
is
characterized
by
an
extensive
fibroinflammatory
microenvironment.
During
carcinogenesis,
normal
stromal
cells
are
converted
to
cytokine-high
cancer-associated
fibroblasts
(CAF).
The
mechanisms
underlying
this
conversion,
including
the
regulation
and
function
of
fibroblast-derived
cytokines,
poorly
understood.
Thus,
efforts
therapeutically
target
CAFs
have
so
far
failed.
Herein,
we
show
that
signals
from
epithelial
expressing
oncogenic
KRAS—a
hallmark
pancreatic
mutation—activate
fibroblast
autocrine
signaling,
which
drives
expression
cytokine
IL33.
Stromal
IL33
remains
high
dependent
on
KRAS
throughout
carcinogenesis;
in
turn,
environmental
stress
induces
interleukin-33
(IL33)
secretion.
Using
compartment-specific
knockout
mice,
observed
lack
leads
profound
reprogramming
multiple
components
tumor
microenvironment,
CAFs,
myeloid
cells,
lymphocytes.
Notably,
loss
increase
CD8+
T-cell
infiltration
activation
and,
ultimately,
reduced
growth.
Significance:
This
study
provides
new
insights
into
programming
shows
during
process,
induced.
CAF-derived
has
pleiotropic
effects
supporting
its
potential
as
a
therapeutic
target.
Biochemical Pharmacology,
Год журнала:
2024,
Номер
229, С. 116492 - 116492
Опубликована: Авг. 15, 2024
Pancreatic
adenocarcinoma
(PDAC)
is
predicted
to
become
the
second
leading
cause
of
cancer
deaths
by
2030
and
this
mostly
due
therapy
failure.
Limited
treatment
options
resistance
standard-of-care
(SoC)
therapies
makes
PDAC
one
types
with
poorest
prognosis
survival
rates
[1,2].
tumors
are
renowned
for
their
poor
response
therapeutic
interventions
including
targeted
therapies,
chemotherapy
radiotherapy.
Herein,
we
review
hallmarks
in
current
strategies
aiming
tackle
escape
mechanisms
re-sensitize
cells
therapy.
We
will
further
provide
insights
on
recent
advances
field
drug
discovery,
nanomedicine,
disease
models
that
setting
ground
future
research.
Journal of Clinical Investigation,
Год журнала:
2024,
Номер
134(12)
Опубликована: Июнь 16, 2024
Although
cancer
has
long
been
considered
a
genetic
disease,
increasing
evidence
shows
that
epigenetic
aberrations
play
crucial
role
in
affecting
tumor
biology
and
therapeutic
response.
The
dysregulated
epigenome
cells
reprograms
the
immune
landscape
within
microenvironment,
thereby
hindering
antitumor
immunity,
promoting
progression,
inducing
immunotherapy
resistance.
Targeting
epigenetically
mediated
tumor-immune
crosstalk
is
an
emerging
strategy
to
inhibit
progression
circumvent
limitations
of
current
immunotherapies,
including
checkpoint
inhibitors.
In
this
Review,
we
discuss
mechanisms
by
which
regulate
interactions
how
targeted
therapies
synergize
with
immunotherapy.
Trends in Cell Biology,
Год журнала:
2024,
Номер
34(10), С. 854 - 864
Опубликована: Фев. 13, 2024
Metazoan
organisms
are
heterocellular
systems
composed
of
hundreds
different
cell
types,
which
arise
from
an
isogenic
genome
through
differentiation.
Cellular
'plasticity'
further
enables
cells
to
alter
their
fate
in
response
exogenous
cues
and
is
involved
a
variety
processes,
such
as
wound
healing,
infection,
cancer.
Recent
advances
cellular
model
systems,
high-dimensional
single-cell
technologies,
lineage
tracing
have
sparked
renaissance
plasticity
research.
Here,
we
discuss
the
definition
plasticity,
evaluate
state-of-the-art
techniques
study
cell-fate
dynamics,
explore
application
technologies
obtain
functional
insights
into
healthy
diseased
tissues.
The
integration
advanced
biomimetic
high-throughput
perturbation
studies
enabling
new
era
research
non-genetic
metazoan
systems.
