Pooled CRISPR screening in pancreatic cancer cells implicates co-repressor complexes as a cause of multiple drug resistance via regulation of epithelial-to-mesenchymal transition.
Antineoplastic Agents
/ pharmacology
CRISPR-Cas Systems
/ genetics
Carcinoma, Pancreatic Ductal
/ drug therapy
Cell Line, Tumor
Cell Movement
/ genetics
Chromatin Immunoprecipitation Sequencing
Co-Repressor Proteins
/ genetics
Drug Resistance, Multiple
/ genetics
Drug Resistance, Neoplasm
/ genetics
Epithelial-Mesenchymal Transition
/ genetics
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Histone Deacetylase 1
/ genetics
Humans
Pancreatic Neoplasms
/ drug therapy
RNA-Seq
ABCG2
CRISPR
Drug resistance
Genome-wide screen
HDAC1
Pancreatic cancer
Precision oncology
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
29 May 2021
29 May 2021
Historique:
received:
17
01
2021
accepted:
17
05
2021
entrez:
29
5
2021
pubmed:
30
5
2021
medline:
16
10
2021
Statut:
epublish
Résumé
Pancreatic ductal adenocarcinoma (PDAC) patients suffer poor outcomes, including a five-year survival of below 10%. Poor outcomes result in part from therapeutic resistance that limits the impact of cytotoxic first-line therapy. Novel therapeutic approaches are needed, but currently no targeted therapies exist to treat PDAC. To assess cellular resistance mechanisms common to four cytotoxic chemotherapies (gemcitabine, 5-fluorouracil, irinotecan, and oxaliplatin) used to treat PDAC patients, we performed four genome-wide CRISPR activation (CRISPR Our data revealed activation of ABCG2, a well-described efflux pump, as the most consistent mediator of resistance in each of our screens. CRISPR-mediated activation of genes involved in transcriptional co-repressor complexes also conferred resistance to multiple drugs. Expression of many of these genes, including HDAC1, is associated with reduced survival in PDAC patients. Up-regulation of HDAC1 in vitro increased promoter occupancy and expression of several genes involved in the epithelial-to-mesenchymal transition (EMT). These cells also displayed phenotypic changes in cellular migration consistent with activation of the EMT pathway. The expression changes resulting from HDAC1 activation were also observed with activation of several other co-repressor complex members. Finally, we developed a publicly available analysis tool, PancDS, which integrates gene expression profiles with our screen results to predict drug sensitivity in resected PDAC tumors and cell lines. Our results provide a comprehensive resource for identifying cellular mechanisms of drug resistance in PDAC, mechanistically implicate HDAC1, and co-repressor complex members broadly, in multi-drug resistance, and provide an analytical tool for predicting treatment response in PDAC tumors and cell lines.
Sections du résumé
BACKGROUND
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) patients suffer poor outcomes, including a five-year survival of below 10%. Poor outcomes result in part from therapeutic resistance that limits the impact of cytotoxic first-line therapy. Novel therapeutic approaches are needed, but currently no targeted therapies exist to treat PDAC.
METHODS
METHODS
To assess cellular resistance mechanisms common to four cytotoxic chemotherapies (gemcitabine, 5-fluorouracil, irinotecan, and oxaliplatin) used to treat PDAC patients, we performed four genome-wide CRISPR activation (CRISPR
RESULTS
RESULTS
Our data revealed activation of ABCG2, a well-described efflux pump, as the most consistent mediator of resistance in each of our screens. CRISPR-mediated activation of genes involved in transcriptional co-repressor complexes also conferred resistance to multiple drugs. Expression of many of these genes, including HDAC1, is associated with reduced survival in PDAC patients. Up-regulation of HDAC1 in vitro increased promoter occupancy and expression of several genes involved in the epithelial-to-mesenchymal transition (EMT). These cells also displayed phenotypic changes in cellular migration consistent with activation of the EMT pathway. The expression changes resulting from HDAC1 activation were also observed with activation of several other co-repressor complex members. Finally, we developed a publicly available analysis tool, PancDS, which integrates gene expression profiles with our screen results to predict drug sensitivity in resected PDAC tumors and cell lines.
CONCLUSION
CONCLUSIONS
Our results provide a comprehensive resource for identifying cellular mechanisms of drug resistance in PDAC, mechanistically implicate HDAC1, and co-repressor complex members broadly, in multi-drug resistance, and provide an analytical tool for predicting treatment response in PDAC tumors and cell lines.
Identifiants
pubmed: 34049503
doi: 10.1186/s12885-021-08388-1
pii: 10.1186/s12885-021-08388-1
pmc: PMC8164247
doi:
Substances chimiques
Antineoplastic Agents
0
Co-Repressor Proteins
0
HDAC1 protein, human
EC 3.5.1.98
Histone Deacetylase 1
EC 3.5.1.98
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
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