Abstract
Pancreatic ductal adenocarcinoma (PDA) cells reprogram their transcriptional and metabolic programs to survive the nutrient-poor tumor microenvironment. Through in vivo CRISPR screening, we discovered islet-2 (ISL2) as a candidate tumor suppressor that modulates aggressive PDA growth. Notably, ISL2, a nuclear and chromatin-associated transcription factor, is epigenetically silenced in PDA tumors and high promoter DNA methylation or its reduced expression correlates with poor patient survival. The exogenous ISL2 expression or CRISPR-mediated upregulation of the endogenous loci reduces cell proliferation. Mechanistically, ISL2 regulates the expression of metabolic genes, and its depletion increases oxidative phosphorylation (OXPHOS). As such, ISL2-depleted human PDA cells are sensitive to the inhibitors of mitochondrial complex I in vitro and in vivo. Spatial transcriptomic analysis shows heterogeneous intratumoral ISL2 expression, which correlates with the expression of critical metabolic genes. These findings nominate ISL2 as a putative tumor suppressor whose inactivation leads to increased mitochondrial metabolism that may be exploitable therapeutically.
Original language | English (US) |
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Pages (from-to) | 1331-1346.e9 |
Journal | Developmental Cell |
Volume | 57 |
Issue number | 11 |
DOIs | |
State | Published - Jun 6 2022 |
Funding
The study was initially funded by a pilot project award (to Dr. Adli and Dr. Bauer) from the University of Virginia Cancer Center . Additionally, the research was supported by Pinn Scholar Award (Dr. Adli) and Reaumond Foundation Award (Dr. Adli). The library used in this study was a kind gift from Dr. Birsoy (now at Rockefeller University). We are thankful to all the members of Adli lab for critical discussions during this study. The study was initially funded by a pilot project award (to Dr. Adli and Dr. Bauer) from the University of Virginia Cancer Center. Additionally, the research was supported by Pinn Scholar Award (Dr. Adli) and Reaumond Foundation Award (Dr. Adli). The library used in this study was a kind gift from Dr. Birsoy (now at Rockefeller University). We are thankful to all the members of Adli lab for critical discussions during this study. M.A. conceptualized the study, supervised the experiments, and wrote the manuscript. C.K. performed the initial screenings. H.C. and T.T. performed the validation and mechanistic investigations. G.C. helped with some of the in vitro experiments. J.Y. M.K. H.O. and Y.B. performed the computational analysis. S.J.A. and B.J.G. in consultation with T.W.B. conducted in vivo screening experiments. S.N. and D.F.K. helped with metabolic assays. T.B.W. and K.-l.H. helped with the LC-MS experiment. K.S.T. and N.B. helped with the organoid and in vivo experiments in the syngeneic mouse model. W.L.H. and D.T.T. helped with the spatial transcriptomic analysis. The authors declare no competing interests.
Keywords
- CRISPR
- ISL2
- pancreatic cancer
- tumor suppressor
ASJC Scopus subject areas
- Molecular Biology
- General Biochemistry, Genetics and Molecular Biology
- Developmental Biology
- Cell Biology