Reversal of lineage plasticity in RB1/TP53-deleted prostate cancer through FGFR and Janus kinase inhibition

Description: Summary from GEO:

"The inherent plasticity of tumor cells provides a mechanism of resistance to many molecularly targeted therapies, exemplified by adeno-to-neuroendocrine lineage transitions seen in prostate and lung cancer. Here we investigate the root cause of this lineage plasticity in a primary murine prostate organoid model that mirrors the lineage transition seen in patients. These cells lose luminal identity within weeks following deletion of Trp53 and Rb1, ultimately acquiring an Ar-negative, Syp+ phenotype after orthotopic in vivo transplantation. Single-cell transcriptomic analysis revealed progressive mixing of luminal-basal lineage features after tumor suppressor gene deletion, accompanied by activation of Jak/Stat and Fgfr pathway signaling and interferon-a and -g gene expression programs prior to any morphologic changes. Genetic or pharmacologic inhibition of Jak1/2 in combination with FGFR blockade restored luminal differentiation and sensitivity to antiandrogen therapy in models with residual AR expression. Collectively, we show lineage plasticity initiates quickly as a largely cell-autonomous process and, through newly developed computational approaches, identify a pharmacological strategy that restores lineage identity using clinical grade inhibitors."

Overall design from GEO:

"Six prostate organoid samples:
Wild-type prostate organoid isolated from TP53 loxP/loxP and RB1 loxP/loxP mice and cultured under standard organoid conditions with dihydrotestosterone (DHT) exposure
Prostate organoid at 2 weeks following cre mediated RB1 and TP53 deletion and cultured under standard organoid conditions with dihydrotestosterone (DHT) exposure
Prostate organoid at 4 weeks following cre mediated RB1 and TP53 deletion and cultured under standard organoid conditions with dihydrotestosterone (DHT) exposure
Prostate organoid at 8 weeks following cre mediated RB1 and TP53 deletion and cultured under standard organoid conditions with dihydrotestosterone (DHT) exposure
Prostate organoid at 4 weeks following cre mediated RB1 and TP53 deletion and cultured under standard organoid conditions withre enzalutamide (ENZ) exposure
Prostate organoid at 8 weeks following cre mediated RB1 and TP53 deletion and cultured under standard organoid conditions withre enzalutamide (ENZ) exposure"

Subject of Study

Mus musculus

Subject(s)

Cell Lineage

Gene Deletion

Genes, Tumor Suppressor

Janus Kinases

Prostatic Neoplasms

Protein-Tyrosine Kinases

Single-Cell Analysis

OncoTree Cancer Type(s)

Prostate Adenocarcinoma
Prostate Neuroendocrine Carcinoma

Access via GEO

Accession #: GSE188318

Access via BioProject

Accession #: PRJNA778250

Access via SRA

Accession #: SRP344808
Access Restrictions: Free to All
Access Instructions: The NCBI Gene Expression Omnibus, BioProject, and SRA databases provide open access to these files.
Associated Publications: Chan J, Karthaus W, Setty M, Love J, Zaidi S, Zhao J, Choo Z, Persad S, LaClair J, Lawrence K, Chaudhary O, Masilionis I, Mazutis L, Chaligne R, Pe'er D, Sawyers C. Reversal of lineage plasticity in RB1/TP53-deleted prostate cancer through FGFR and Janus kinase inhibition. Cancer Research. 2022; 82(12 Suppl.).
Equipment Used: Illumina NovaSeq 6000
Dataset Format(s): CSV, TAR, H5AD
Dataset Size: 3.9 GB

Data Catalog Record Updated: 2023-10-12