Phenotypic
plasticity,
the
capacity
of
cells
to
transition
between
distinct
phenotypic
and
lineage
states
over
time,
is
a
genetically
epigenetically
encoded
trait
essential
for
normal
development
adult
tissue
homeostasis.
In
cancer,
plasticity
programs
can
be
deployed
aberrantly
enable
disease
progression
acquired
therapeutic
resistance.
Cancer
current
barrier
achieving
cures
advanced
cancers
using
available
molecularly
targeted
therapies.
This
review
summarizes
complex
interconnected
molecular
pathways
implicated
in
both
context
homeostasis
cancer.
Molecular
convergent
these
contexts
are
highlighted
while
enabling
distinguished
from
those
that
specify
phenotype
already
plastic
cells.
Key
unresolved
questions
field
discussed
along
with
emerging
technologies
may
used
help
answer
them.
Research Square (Research Square),
Год журнала:
2024,
Номер
unknown
Опубликована: Ноя. 8, 2024
Abstract
Neuroendocrine
prostate
cancer
(NEPC)
presents
a
formidable
clinical
challenge
owing
to
its
aggressive
progression
and
resistance
conventional
therapies.
A
key
driver
of
NEPC
is
the
overexpression
MYCN,
well-established
oncogene
associated
with
neuroendocrine
tumors.
However,
efforts
directly
inhibit
N-Myc
protein
encoded
by
this
gene
have
resulted
in
limited
success,
thereby
hindering
therapeutic
advancements.
To
overcome
obstacle,
we
conducted
unbiased
genome-wide
screening
using
isogenic
cell
lines
identify
synthetic
vulnerabilities
MYCN.
Among
identified
candidates,
NEUROG2
emerged
as
significant
candidate.
Neurog2
proneural
transcription
factor
(PTF)
known
for
role
developmental
processes
trans-differentiation
adult
cells.
Our
findings
demonstrate
that
depletion
does
not
affect
non-malignant
cells,
but
significantly
suppresses
growth
MYCN-overexpressing
cells
tumors
orthotopic
models.
Furthermore,
our
observations
indicate
Neurog2-mediated
regulation
PTFs
can
facilitate
development.
Thus,
targeting
holds
promise
an
effective
strategy
NEPC.
Prostate
cancer
(PCa)
is
characterised
by
androgen-dependency.
Unfortunately,
under
anti-androgen
treatment
pressure,
castration-resistant
prostate
(CRPC)
emerges,
heterogeneous
cell
populations
that,
over
time,
lead
to
the
development
of
different
androgen-dependent
or
-independent
phenotypes.
Despite
important
advances
in
therapeutic
strategies,
CRPC
remains
incurable.
Context-specific
essential
genes
represent
valuable
candidates
for
targeted
anti-cancer
therapies.
Through
investigation
gene
and
protein
annotations
integration
several
published
transcriptomic
data,
we
identified
two
consensus
lists
stratify
PCa
patients'
risk
discriminate
phenotypes
based
on
androgen
receptor
activity.
ROC
Kaplan-Meier
survival
analyses
were
used
set
validation
independent
datasets.
We
further
evaluated
these
their
association
with
dependency.
The
deregulated
expression
PCa-related
was
associated
overall
disease-specific
survival,
metastasis
and/or
high
recurrence
risk,
while
CRPC-related
clearly
discriminated
between
adeno
neuroendocrine
Some
showed
context-specific
essentiality.
candidate
drugs
through
a
computational
repositioning
approach
targeting
treating
lethal
variants
PCa.
This
work
provides
proof-of-concept
use
an
integrative
identify
biomarkers
involved
progression
pathogenesis
within
goal
precision
medicine.
Phenotypic
plasticity,
the
capacity
of
cells
to
transition
between
distinct
phenotypic
and
lineage
states
over
time,
is
a
genetically
epigenetically
encoded
trait
essential
for
normal
development
adult
tissue
homeostasis.
In
cancer,
plasticity
programs
can
be
deployed
aberrantly
enable
disease
progression
acquired
therapeutic
resistance.
Cancer
current
barrier
achieving
cures
advanced
cancers
using
available
molecularly
targeted
therapies.
This
review
summarizes
complex
interconnected
molecular
pathways
implicated
in
both
context
homeostasis
cancer.
Molecular
convergent
these
contexts
are
highlighted
while
enabling
distinguished
from
those
that
specify
phenotype
already
plastic
cells.
Key
unresolved
questions
field
discussed
along
with
emerging
technologies
may
used
help
answer
them.
