EMBO Molecular Medicine,
Год журнала:
2024,
Номер
16(5), С. 1162 - 1192
Опубликована: Апрель 24, 2024
Platinum
(PT)-resistant
Epithelial
Ovarian
Cancer
(EOC)
grows
as
a
metastatic
disease,
disseminating
in
the
abdomen
and
pelvis.
Very
few
options
are
available
for
PT-resistant
EOC
patients,
little
is
known
about
how
acquisition
of
PT-resistance
mediates
increased
spreading
capabilities
EOC.
Here,
using
isogenic
cells,
genetic
pharmacological
approaches,
patient-derived
models,
we
report
that
Integrin
α6
(ITGA6)
overexpressed
by
cells
necessary
to
sustain
ability
adhesion-dependent
PT-resistance.
Using
vitro
showed
PT
induces
positive
loop
that,
stimulating
ITGA6
transcription
secretion,
contributes
formation
pre-metastatic
niche
enabling
disseminate.
At
molecular
level,
engagement
regulates
production
availability
insulin-like
growth
factors
(IGFs),
over-stimulating
IGF1R
pathway
upregulating
Snail
expression.
In
data
were
recapitulated
vivo
models
which
targeting
prevents
dissemination
improves
PT-activity,
supporting
promising
druggable
target
patients.
Endocrine Reviews,
Год журнала:
2022,
Номер
44(2), С. 297 - 311
Опубликована: Окт. 21, 2022
Pituitary
adenomas
(PAs)
are
neoplasms
derived
from
the
endocrine
cells
of
anterior
pituitary
gland.
Most
frequently,
they
benign
tumors,
but
may
sometimes
display
an
aggressive
course,
and
in
some
cases
metastasize.
Their
biology,
including
their
wide
range
behavior,
is
only
partly
understood.
In
terms
therapeutic
targeting,
most
PAs
easily
treated
with
available
medical
treatments,
surgery,
radiotherapy.
Nevertheless,
gonadotroph
lack
options,
treatment
carcinomas
remains
challenging.
Here,
we
present
overview
implications
tumor
microenvironment
PAs,
reviewing
its
composition
function,
as
well
published
that
have
been
thus
far
using
microenvironment-targeting
therapies.
Additionally,
discuss
emerging
views,
such
concept
nonangiogenic
perspectives
regarding
treatments
represent
future
potential
options.
Tumor-infiltrating
lymphocytes,
tumor-associated
macrophages,
folliculostellate
cells,
fibroblasts,
angiogenesis,
extracellular
matrix
remodeling,
all
complex
roles
biology
PAs.
They
linked
to
hormone
production/secretion,
size,
invasion,
proliferation,
progression/recurrence,
response
From
a
perspective,
immune-checkpoint
inhibitors
bevacizumab
already
shown
degree
efficacy
carcinomas,
use
numerous
other
therapies
can
be
foreseen.
conclusion,
similar
cancers,
understanding
improves
our
PA
beyond
genetics
epigenetics,
constitutes
important
tool
for
developing
Cancers,
Год журнала:
2023,
Номер
15(3), С. 628 - 628
Опубликована: Янв. 19, 2023
PDAC
is
an
extremely
aggressive
tumor
with
a
poor
prognosis
and
remarkable
therapeutic
resistance.
The
dense
extracellular
matrix
(ECM)
which
characterizes
progression
considered
fundamental
determinant
of
chemoresistance,
major
contributions
from
mechanical
factors.
This
study
combined
biomechanical
pharmacological
approaches
to
evaluate
the
role
cell-adhesion
molecule
ITGA2,
key
regulator
ECM,
in
resistance
gemcitabine.The
prognostic
value
ITGA2
was
analysed
publicly
available
databases
tissue-microarrays
two
cohorts
radically
resected
metastatic
patients
treated
gemcitabine.
PANC-1
its
gemcitabine-resistant
clone
(PANC-1R)
were
by
RNA-sequencing
label-free
proteomics.
migration,
proliferation,
apoptosis
investigated
using
hydrogel-coated
wells,
siRNA-mediated
knockdown
overexpression,
while
collagen-embedded
spheroids
assessed
invasion
ECM
remodeling.High
expression
correlated
shorter
progression-free
overall
survival,
supporting
impact
on
lack
efficacy
gemcitabine
treatment.
These
findings
corroborated
transcriptomic
proteomic
analyses
showing
that
upregulated
PANC-1R
clone.
behavior
these
cells
significantly
reduced
silencing
both
vitro
vivo,
growing
under
conditions
resembling
stiffness
acquired
gemcitabine,
associated
increased
expression.
Collagen-embedded
showed
significant
remodeling
spreading
potential
via
CXCR4
MMP2.
Additionally,
overexpression
MiaPaCa-2
triggered
upregulation
phospho-AKT.ITGA2
emerged
as
new
factor,
highlighting
relevance
stroma
properties
targets
counteract
PDAC.
Journal of Biomolecular NMR,
Год журнала:
2023,
Номер
77(3), С. 111 - 119
Опубликована: Июнь 1, 2023
Abstract
In
the
last
three
decades,
scope
of
solid-state
NMR
has
expanded
to
exploring
complex
biomolecules,
from
large
protein
assemblies
intact
cells
at
atomic-level
resolution.
This
diversity
in
macromolecules
frequently
features
highly
flexible
components
whose
insoluble
environment
precludes
use
solution
study
their
structure
and
interactions.
While
High-resolution
Magic-Angle
Spinning
(HR-MAS)
probes
offer
capacity
for
gradient-based
1
H-detected
spectroscopy
solids,
such
are
not
commonly
used
routine
MAS
experiments.
As
a
result,
most
exploration
regime
entails
either
13
C-detected
experiments,
partially
perdeuterated
systems,
or
ultra-fast
MAS.
Here
we
explore
proton-detected
pulse
schemes
probing
through-bond
C–
C
networks
mobile
sidechains
as
well
polysaccharides
broadband
manner.
We
demonstrate
mixture
microtubule-associated
(MAP)
tau
human
microtubules
(MTs),
cell
wall
fungus
Schizophyllum
commune
using
2D
3D
spectroscopy,
show
its
viability
obtaining
unambiguous
correlations
standard
fast-spinning
high
ultra-high
magnetic
fields.
Nature Communications,
Год журнала:
2024,
Номер
15(1)
Опубликована: Окт. 24, 2024
Recurrent
breast
cancers
often
develop
resistance
to
standard-of-care
therapies.
Identifying
targetable
factors
contributing
cancer
recurrence
remains
the
rate-limiting
step
in
improving
long-term
outcomes.
In
this
study,
we
identify
tumor
cell-derived
osteopontin
as
an
autocrine
and
paracrine
driver
of
recurrence.
Osteopontin
promotes
cell
proliferation,
recruits
macrophages,
synergizes
with
IL-4
further
polarize
them
into
a
pro-tumorigenic
state.
Macrophage
depletion
inhibition
decrease
recurrent
growth.
Furthermore,
targeting
primary
tumor-bearing
female
mice
prevents
metastasis,
permits
T
infiltration
activation,
improves
anti-PD-1
immunotherapy
response.
Clinically,
expression
is
higher
metastatic
tumors
versus
patient-matched
tumors.
positively
correlates
macrophage
infiltration,
increases
grade,
its
elevated
pathway
activity
associated
poor
prognosis
Our
findings
suggest
clinical
implications
alternative
therapeutic
strategy
based
on
osteopontin's
multiaxial
role
progression
Frontiers in Cell and Developmental Biology,
Год журнала:
2025,
Номер
13
Опубликована: Март 18, 2025
The
mechanical
properties
of
the
tumor
microenvironment
(TME)
undergo
significant
changes
during
growth,
primarily
driven
by
alterations
in
extracellular
(ECM)
stiffness
and
viscoelasticity.
These
not
only
promote
progression
but
also
hinder
therapeutic
efficacy
impairing
drug
delivery
activating
mechanotransduction
pathways
that
regulate
crucial
cellular
processes
such
as
migration,
proliferation,
resistance
to
therapy.
In
this
review,
we
examine
mechanisms
through
which
cells
sense
transmit
signals
maintain
homeostasis
biomechanically
altered
TME.
We
explore
current
computational
modelling
strategies
for
pathways,
highlighting
need
developing
models
incorporate
additional
components
mechanosignaling
machinery.
Furthermore,
review
available
methods
measuring
tumors
clinical
settings
aiming
at
restoring
TME
blocking
deregulated
pathways.
Finally,
propose
proper
characterization
a
deeper
understanding
landscape
TME,
both
tissue
levels,
are
essential
account
influence
forces
on
treatment
efficacy.
International Journal of Translational Medicine,
Год журнала:
2022,
Номер
2(3), С. 419 - 447
Опубликована: Авг. 19, 2022
Despite
significant
advances
in
the
understanding
of
cancer
biology,
is
still
a
leading
cause
death
worldwide.
Expression
tumor
microenvironment
component,
osteopontin,
tissues,
plasma,
and
serum,
has
been
shown
to
be
associated
with
poor
prognosis
survival
rate
various
human
cancers.
Recent
studies
suggest
that
osteopontin
drives
development
aggressiveness
using
strategies.
In
this
review,
we
first
provide
an
overview
how
promotes
progression,
such
as
growth,
invasion,
angiogenesis,
immune
modulation,
well
metastasis
chemoresistance.
Next,
address
functional
activities
are
modulated
by
interaction
integrins
CD44
receptors,
but
also
post-translational
modification,
proteolytic
processing
several
proteases,
phosphorylation,
glycosylation.
Then,
review
activates
tumor-associated
macrophages
(TAMs)
cancer-associated
fibroblasts
(CAFs),
functions
immunosuppressor
regulating
surveillance
checkpoint
microenvironment.
Finally,
discuss
potential
applications
biomarker
therapeutic
target.
Annals of the Rheumatic Diseases,
Год журнала:
2023,
Номер
82(11), С. 1474 - 1486
Опубликована: Июль 21, 2023
Activation
of
fibroblasts
is
a
hallmark
fibrotic
processes.
Besides
cytokines
and
growth
factors,
are
regulated
by
the
extracellular
matrix
environment
through
receptors
such
as
integrins,
which
transduce
biochemical
mechanical
signals
enabling
cells
to
mount
appropriate
responses
according
biological
demands.
The
aim
this
work
was
investigate
in
vivo
role
collagen-fibroblast
interactions
for
regulating
fibroblast
functions
fibrosis.Triple
knockout
(tKO)
mice
with
combined
ablation
integrins
α1β1,
α2β1
α11β1
were
created
address
significance
integrin-mediated
cell-collagen
communication.
Properties
primary
dermal
lacking
collagen-binding
delineated
vitro.
Response
tKO
skin
bleomycin
induced
challenge
assessed.Triple
integrin-deficient
develop
normally,
transiently
smaller
reveal
mild
alterations
mechanoresilience
skin.
Fibroblasts
from
these
culture
show
defects
cytoskeletal
architecture,
traction
stress
generation,
production
organisation.
Ablation
three
leads
increased
levels
discoidin
domain
receptor
2,
an
alternative
recognising
collagens
However,
overexpression
fails
compensate
adhesion
spreading
on
collagen
substrates
Mice
severely
attenuated
response
impaired
mechanotransduction,
reduced
organisation.The
data
provide
evidence
crucial
force
generation
differentiation
vitro
deposition
tissue
remodelling
vivo.
Targeting
fibroblast-collagen
might
represent
promising
therapeutic
approach
regulate
connective
diseases.
Journal for ImmunoTherapy of Cancer,
Год журнала:
2023,
Номер
11(12), С. e007447 - e007447
Опубликована: Дек. 1, 2023
Background
One
reason
patients
with
cancer
cannot
benefit
from
immunotherapy
is
the
lack
of
immune
cell
infiltration
in
tumor
tissues.
Cancer-associated
fibroblasts
(CAFs)
are
emerging
as
central
players
regulation
that
shapes
microenvironment
(TME).
Earlier
we
reported
integrin
α5
was
enriched
CAFs
colorectal
(CRC),
however,
its
role
TME
and
remains
unclear.
Here,
aimed
to
investigate
for
modulating
antitumor
immunity
therapeutic
efficacy
combined
checkpoint
blockade
CRC.
Methods
We
analyzed
CRC
single-cell
RNA
sequencing
(scRNA-seq)
database
define
expression
ITGA5
stroma.
Experimentally,
carried
out
vivo
mouse
xenograft
models
confirm
targeting
α5β1
inhibition
anti-Programmed
death
ligand
1
(PD-L1)
vitro
cell-co-culture
assay
affecting
T-cell
activity.
Clinically,
association
between
infiltrating
T
cells
evaluated
their
correlation
patient
survival
prognosis
Results
revealed
FAP
-CAFs.
Both
knockout
improved
response
anti-PD-L1
treatment
subcutaneous
models.
Mechanistically,
these
treatments
led
increased
tumor-infiltrating
CD8
+
cells.
Furthermore,
found
correlated
extracellular
matrix
(ECM)-related
genes
affected
ECM
deposition
analysis
culture
killing
experiment
showed
proteins
influence
confirmed
high
associated
fewer
CD3
cells,
tissues
low
levels
better
a
cohort
29
patients.
Conclusions
Our
study
identified
by
PD-L1