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EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance

UID: 11170

Author(s): Chibaya, Loretah, Murphy, Katherine C., DeMarco, Kelly D., Gopalan, Sneha, Liu, Haibo, Parikh, Chaitanya N., Lopez-Diaz, Yvette, Faulkner, Melissa, Li, Junhui, Morris IV, John P.*, Ho, Yu-jui*, Chana, Sachliv K., Simon, Janelle*, Luan, Wei*, Kulick, Amanda*, de Stanchina, Elisa*, Simin, Karl, Zhu, Lihua, Fazzio, Thomas, Lowe, Scott W.*, Ruscetti, Marcus* * MSK affiliated

Description
Summary from GEO:

"Immunotherapies that produce durable responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of the senescence-associated secretory phenotype (SASP) can be an effective approach to activate anti-tumor Natural Killer (NK) and T cell immunity. Here we found the pancreas tumor microenvironment (TME) suppresses NK and T cell surveillance following therapy-induced senescence through EZH2-mediated epigenetic repression of pro-inflammatory SASP genes. EZH2 blockade stimulated production of SASP chemokines CCL2 and CXCL9/10, leading to enhanced NK and T cell infiltration and PDAC eradication in mouse models. EZH2 activity was also associated with suppression of chemokine signaling and cytotoxic lymphocytes and reduced survival in PDAC patients. These results demonstrate that EZH2 represses of the pro-inflammatory SASP, and that EZH2 inhibition combined with senescence-inducing therapy could be a powerful means to achieve immune-mediated tumor control in PDAC."

Overall design from GEO:

"For RNA-seq analysis of PIP, PIL, LIL, and LIP tumor samples, GFP+ tumor cells were FACS sorted on a FACSAria (BD Biosciences) from the lungs or pancreas of tumor-bearing mice following 2-week treatment with vehicle or combined trametinib (1 mg/kg body weight) and palbociclib (100 mg/kg). Total RNA was extracted from tumor cells using the RNeasy Mini Kit (Qiagen). Purified polyA mRNA was subsequently fragmented, and first and second strand cDNA synthesis performed using standard Illumina mRNA TruSeq library preparation protocols. Double stranded cDNA was subsequently processed for TruSeq dual-index Illumina library generation. For sequencing, pooled multiplexed libraries were run on a HiSeq 2500 machine on RAPID mode. Approximately 10 million 76bp single-end reads were retrieved per replicate condition. RNA-Seq data was analyzed by removing adaptor sequences using Trimmomatic, version 0.36, aligning sequencing data to GRCm38 (Ensembl, version 101) with STAR, version 2.5.3a, and genome wide transcript counting using featureCounts, version 1.6.3 to generate a RPKM matrix of transcript counts. Genes were identified as differentially expressed using R package DESeq2, version 1.28.1 with a cutoff of absolute log2FoldChange ≥ 1 and adjusted p-value
Subject of Study
Mus musculus
Subject(s)
Carcinoma, Pancreatic Ductal
Enhancer of Zeste Homolog 2 Protein
Pancreatic Neoplasms
RNA-Seq
Senescence-Associated Secretory Phenotype
T-Lymphocytes
OncoTree Cancer Type(s)
Pancreatic Adenocarcinoma
Access via GEO


Accession #: GSE201495

Access via BioProject


Accession #: PRJNA831880

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus and BioProject databases provide open access to these files.
Associated Publications
Chibaya L, Murphy K, DeMarco K, Gopalan S, Liu H, Parikh C, Lopez-Diaz Y, Faulkner M, Li J, Morris J, Ho Y, Chana S, Simon J, Luan W, Kulick A, de Stanchina E, Simin K, Zhu L, Fazzio T, Lowe S, Ruscetti M. EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance. Nature Cancer. 2023; 4(6):872-892.
Equipment Used
Illumina HiSeq 2500

High throughput sequencing system

Dataset Format(s)
CSV
Dataset Size
4.7 MB
Data Catalog Record Updated
2024-02-23