Cancer Discovery,
Journal Year:
2024,
Volume and Issue:
14(7), P. 1276 - 1301
Published: March 26, 2024
Abstract
Cancer
homeostasis
depends
on
a
balance
between
activated
oncogenic
pathways
driving
tumorigenesis
and
engagement
of
stress
response
programs
that
counteract
the
inherent
toxicity
such
aberrant
signaling.
Although
inhibition
signaling
has
been
explored
extensively,
there
is
increasing
evidence
overactivation
same
can
also
disrupt
cancer
cause
lethality.
We
show
here
protein
phosphatase
2A
(PP2A)
hyperactivates
multiple
engages
responses
in
colon
cells.
Genetic
compound
screens
identify
combined
PP2A
WEE1
as
synergistic
models
by
collapsing
DNA
replication
triggering
premature
mitosis
followed
cell
death.
This
combination
suppressed
growth
patient-derived
tumors
vivo.
Remarkably,
acquired
resistance
to
this
drug
ability
cells
form
Our
data
suggest
paradoxical
activation
result
tumor-suppressive
resistance.
Significance:
A
therapy
consisting
deliberate
hyperactivation
with
perturbation
from
very
effective
animal
cancer.
Resistance
associated
loss
reduced
capacity,
indicative
Nature,
Journal Year:
2023,
Volume and Issue:
622(7983), P. 584 - 593
Published: June 27, 2023
Abstract
The
human
embryo
undergoes
morphogenetic
transformations
following
implantation
into
the
uterus,
but
our
knowledge
of
this
crucial
stage
is
limited
by
inability
to
observe
in
vivo.
Models
derived
from
stem
cells
are
important
tools
for
interrogating
developmental
events
and
tissue–tissue
crosstalk
during
these
stages
1
.
Here
we
establish
a
model
post-implantation
embryo,
embryoid,
comprising
embryonic
extraembryonic
tissues.
We
combine
two
types
extraembryonic-like
cell
generated
overexpression
transcription
factors
with
wild-type
promote
their
self-organization
structures
that
mimic
several
aspects
embryo.
These
self-organized
aggregates
contain
pluripotent
epiblast-like
domain
surrounded
Our
functional
studies
demonstrate
robustly
differentiates
amnion,
mesenchyme
primordial
germ
cell-like
response
bone
protein
cues.
In
addition,
identify
an
inhibitory
role
SOX17
specification
anterior
hypoblast-like
2
Modulation
subpopulations
compartment
demonstrates
influence
differentiation,
highlighting
crosstalk.
conclusion,
present
modular,
tractable,
integrated
3
will
enable
us
probe
key
questions
development,
critical
window
which
substantial
numbers
pregnancies
fail.
Nature Communications,
Journal Year:
2023,
Volume and Issue:
14(1)
Published: July 26, 2023
Abstract
Ulcerative
colitis
and
Crohn’s
disease
are
chronic
inflammatory
intestinal
diseases
with
perplexing
heterogeneity
in
manifestation
response
to
treatment.
While
the
molecular
basis
for
this
remains
uncharacterized,
single-cell
technologies
allow
us
explore
transcriptional
states
within
tissues
at
an
unprecedented
resolution
which
could
further
understanding
of
these
complex
diseases.
Here,
we
apply
RNA-sequencing
human
inflamed
intestine
show
that
largest
differences
among
patients
present
myeloid
compartment
including
macrophages
neutrophils.
Using
spatial
transcriptomics
tissue
(CosMx
Spatial
Molecular
Imaging)
spatially
localize
each
macrophage
neutrophil
subsets
identified
by
unravel
diversity
based
on
their
localization.
Finally,
combined
analysis
reveals
a
strong
communication
network
involving
fibroblasts.
Our
data
sheds
light
cellular
complexity
points
towards
stromal
compartments
as
important
patient-to-patient
heterogeneity.
Nature Communications,
Journal Year:
2023,
Volume and Issue:
14(1)
Published: Feb. 13, 2023
The
tumor
microenvironment
(TME)
in
pancreatic
ductal
adenocarcinoma
(PDAC)
is
a
complex
ecosystem
that
drives
progression;
however,
in-depth
single
cell
characterization
of
the
PDAC
TME
and
its
role
response
to
therapy
lacking.
Here,
we
perform
single-cell
RNA
sequencing
on
freshly
collected
human
samples
either
before
or
after
chemotherapy.
Overall,
find
heterogeneous
mixture
basal
classical
cancer
subtypes,
along
with
distinct
cancer-associated
fibroblast
macrophage
subpopulations.
Strikingly,
basal-like
cells
exhibit
similar
transcriptional
responses
chemotherapy
do
not
demonstrate
shift
towards
program
among
treated
samples.
We
observe
decreased
ligand-receptor
interactions
samples,
particularly
between
TIGIT
CD8
+
T
receptor
cells,
identify
as
major
inhibitory
checkpoint
molecule
cells.
Our
results
suggest
profoundly
impacts
may
promote
resistance
immunotherapy.
Science Immunology,
Journal Year:
2022,
Volume and Issue:
7(73)
Published: July 1, 2022
Various
lung
insults
can
result
in
replacement
of
resident
alveolar
macrophages
(AM)
by
bone
marrow
monocyte–derived
(BMo)–AM.
However,
the
dynamics
this
process
and
its
long-term
consequences
for
respiratory
viral
infections
remain
unclear.
Using
several
mouse
models
a
marker
to
unambiguously
track
fetal
(FeMo)–AM
BMo-AM,
we
established
kinetics
extent
replenishment
their
function
recurrent
influenza
A
virus
(IAV)
infection.
massive
loss
FeMo-AM
resulted
rapid
self-renewal
survivors,
followed
generation
BMo-AM.
BMo-AM
progressively
outcompeted
over
months,
was
due
increased
glycolytic
proliferative
capacity.
The
presence
both
naïve
experienced
conferred
severe
pathology
IAV
infection,
which
associated
with
proinflammatory
phenotype.
Furthermore,
upon
aging
mice,
were
gradually
replaced
contributed
disease
severity
cell-autonomous
manner.
Together,
our
results
suggest
that
origin
rather
than
training
AM
determines
infection
provide
an
explanation
seen
elderly.
Nature Communications,
Journal Year:
2023,
Volume and Issue:
14(1)
Published: March 15, 2023
Abstract
To
date,
single-cell
studies
of
human
white
adipose
tissue
(WAT)
have
been
based
on
small
cohort
sizes
and
no
cellular
consensus
nomenclature
exists.
Herein,
we
performed
a
comprehensive
meta-analysis
publicly
available
newly
generated
single-cell,
single-nucleus,
spatial
transcriptomic
results
from
subcutaneous,
omental,
perivascular
WAT.
Our
high-resolution
map
is
built
data
ten
allowed
us
to
robustly
identify
>60
subpopulations
adipocytes,
fibroblast
adipogenic
progenitors,
vascular,
immune
cells.
Using
these
results,
deconvolved
bulk
nine
additional
cohorts
provide
clinical
dimensions
the
map.
This
identified
cell-cell
interactions
as
well
relationships
between
specific
cell
subtypes
insulin
resistance,
dyslipidemia,
adipocyte
volume,
lipolysis
upon
long-term
weight
changes.
Altogether,
our
meta-map
provides
rich
resource
defining
microarchitectural
landscape
WAT
describes
associations
types
metabolic
states.
