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Developmentally constrained plasticity as a therapeutic vulnerability in cancer
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DOI：10.1016/j.neo.2026.101344.png)
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Abstract
En 中文
• Adult tissues keep constrained cell states during homeostasis, repair, chronic injury and aging. • Cell of origin sets tumor plasticity limits and shapes drug resistance profiles. • Drug resistance includes lineage retention, adaptive reversal and stable reprogramming. • Omics identify plastic cell states; only functional tests confirm phenotype reversibility. • Prime-then-kill is a state-contingent strategy, not a rigid treatment algorithm.
Keywords:
Cancer plasticity
Cell of origin
Developmental constraint
Drug-tolerant persisters
Lineage switching
Therapeutic resistance
AC
Astrocyte-like
ADC
Antibody-drug conjugate
AR
Androgen receptor
ARPI
Androgen receptor pathway inhibitor
AT2
Alveolar type 2
BC
Breast cancer
CAF
Cancer-associated fibroblast
CD3
Cluster of differentiation 3
CRC
Colorectal cancer
CRPC
Castration-resistant prostate cancer
CTL
Cytotoxic T lymphocyte
DDI
Developmental diversity index
DNMT
DNA methyltransferase
DNPC
Double-negative prostate cancer
DTP
Drug-tolerant persister
EGFR
Epidermal growth factor receptor
EMT
Epithelial-to-mesenchymal transition
ER
Estrogen receptor
FGFR3
Fibroblast growth factor receptor 3
GalNAc
N-acetylgalactosamine
GBM
Glioblastoma
H3K4me3
Histone H3 lysine 4 trimethylation
H3K27me3
Histone H3 lysine 27 trimethylation
HCC
Hepatocellular carcinoma
HDAC
Histone deacetylase
HPCS
High-plasticity cell state
ICI
Immune checkpoint inhibitor
IFN
Interferon
JAK/STAT
Janus kinase/signal transducer and activator of transcription
LSD1
Lysine-specific demethylase 1
LUAD
Lung adenocarcinoma
MAPK
Mitogen-activated protein kinase
MAPKi
MAPK inhibitor
mCRPC
Metastatic castration-resistant prostate cancer
MES
Mesenchymal-like
MHC-I
Major histocompatibility complex class I
NE
Neuroendocrine
NEPC
Neuroendocrine prostate cancer
NPC
Neural progenitor-like
NSCLC
Non-small-cell lung cancer
OPC
Oligodendrocyte progenitor-like
PCa
Prostate cancer
PD
Pharmacodynamic
PDAC
Pancreatic ductal adenocarcinoma
PRC2
Polycomb repressive complex 2
PSA
Prostate-specific antigen
scATAC-seq
Single-cell ATAC sequencing
scRNA-seq
Single-cell RNA sequencing
SCLC
Small-cell lung cancer
SCNPC
Small-cell neuroendocrine prostate cancer
TGF-β
Transforming growth factor beta
TKI
Tyrosine kinase inhibitor
TME
Tumor microenvironment
t-NEPC
Treatment-emergent neuroendocrine prostate cancer
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