PKN2 is a dependency of the mesenchymal-like cancer cell state

Cancer Discovery, Journal Year: 2024, Volume and Issue: 15(3), P. 595 - 615

Published: Nov. 19, 2024

Cancer cells exploit a mesenchymal-like transcriptional state (MLS) to survive drug treatments. Although the MLS is well characterized, few therapeutic vulnerabilities targeting this program have been identified. In study, we systematically identify dependency network of cancers through an analysis gene essentiality scores in ∼800 cancer cell lines, nominating poorly studied kinase, PKN2, as top target MLS. Coessentiality relationships, biochemical experiments, and genomic analyses patient tumors revealed that PKN2 promotes growth PKN2-SAV1-TAZ signaling mechanism. Notably, pairing genetic inhibition with clinically relevant targeted therapies against EGFR, KRAS, BRAF suppresses resistance by depleting drug-tolerant persister cells. These findings provide evidence core regulator Hippo tumor suppressor pathway highlight potential generalizable strategy overcome driven across contexts. Significance: This work identifies member pathway, its blocks YAP/TAZ-driven tumorigenesis. Furthermore, study discovers PKN2-TAZ arguably most selective supports specific provocative diverse See related commentary Shen Tan, p. 458.

Language: Английский

The molecular determinants of phenotypic plasticity in homeostasis and neoplasia

Published: Dec. 13, 2024

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.

Language: Английский

Dynamic Plasticity Systems Direct Early Adaptation to Treatment in Neuroblastoma

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Dec. 8, 2023

Abstract In paediatric cancers like neuroblastoma, limited genetic diversity emphasizes the role of phenotypic heterogeneity in driving malignancy. We investigated this phenomenon using experimental evolution and single-cell techniques neuroblastoma preclinical models. Our findings reveal that cells navigate multistable landscapes, named plasticity systems. These finely regulate their topology dynamics enabling tolerance, persistence, regrowth response to treatment. While preferential killing adrenergic (ADRN), notably under cisplatin treatment, enriches drug-tolerant persister (DTP) populations with mesenchymal (MES) properties, we also observed transitions contributing DTP entry exit. Additionally, single-cell-derived clone experiments unveiled a spectrum heritable traits linked functional influencing behaviour. Mathematical modelling supports critical all cell phenotypes evolutionary adaptation. Collectively, our study depicts systems as key early cancer drivers adaptive through regulating multistability landscapes. insights underscore necessity decoding for advancing long-term therapeutic effectiveness.

Language: Английский