Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer

Linara Gabitova-Cornell; Aizhan Surumbayeva; Suraj Peri; Janusz Franco-Barraza; Diana Restifo; N Weitz; Charline Ogier; AR Goldman; Tiffiney R. Hartman; R. Francescone; Y Tan; Emmanuelle Nicolas; N. Shah; Elizabeth Handorf; Kathy Cai; Alana M. O'Reilly; I Sloma; Rachel Chiaverelli; RA Moffitt; V Khazak; Carolyn Y. Fang; Erica A. Golemis; Edna Cukierman; Igor Astsaturov

doi:10.1016/j.ccell.2020.08.015

Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer

Linara Gabitova-Cornell, Aizhan Surumbayeva, Suraj Peri, Janusz Franco-Barraza, Diana Restifo, N Weitz, Charline Ogier, AR Goldman, Tiffiney R. Hartman, R. Francescone, Y Tan, Emmanuelle Nicolas, N. Shah, Elizabeth Handorf, Kathy Cai, Alana M. O'Reilly, I Sloma, Rachel Chiaverelli, RA Moffitt, V KhazakCarolyn Y. Fang, Erica A. Golemis, Edna Cukierman, Igor Astsaturov

Research output: Contribution to journal › Article › peer-review

113 Scopus citations

Abstract

Oncogenic transformation alters lipid metabolism to sustain tumor growth. We define a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of the rate-limiting enzyme Nsdhl or treatment with cholesterol-lowering statins switches glandular pancreatic carcinomas to a basal (mesenchymal) phenotype in mouse models driven by Kras^G12D expression and homozygous Trp53 loss. Consistently, PDACs in patients receiving statins show enhanced mesenchymal features. Mechanistically, statins and NSDHL loss induce SREBP1 activation, which promotes the expression of Tgfb1, enabling epithelial-mesenchymal transition. Evidence from patient samples in this study suggests that activation of transforming growth factor β signaling and epithelial-mesenchymal transition by cholesterol-lowering statins may promote the basal type of PDAC, conferring poor outcomes in patients.

Original language	English
Pages (from-to)	567-583.e11
Journal	Cancer Cell
Volume	38
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2020.08.015
State	Published - Oct 12 2020

Keywords

3-Hydroxysteroid Dehydrogenases/genetics
Animals
Atorvastatin/pharmacology
Biosynthetic Pathways/genetics
Carcinoma, Pancreatic Ductal/drug therapy
Cell Differentiation/drug effects
Cell Line, Tumor
Cholesterol, LDL/biosynthesis
Epithelial-Mesenchymal Transition/drug effects
Gene Expression Profiling
Gene Expression Regulation, Neoplastic/drug effects
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
Kaplan-Meier Estimate
Mice, Inbred C57BL
Mice, Knockout
Pancreatic Neoplasms/drug therapy
Signal Transduction/genetics
Transforming Growth Factor beta/genetics
Xenograft Model Antitumor Assays/methods

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccell.2020.08.015

Cite this

Gabitova-Cornell, L., Surumbayeva, A., Peri, S., Franco-Barraza, J., Restifo, D., Weitz, N., Ogier, C., Goldman, AR., Hartman, T. R., Francescone, R., Tan, Y., Nicolas, E., Shah, N., Handorf, E., Cai, K., O'Reilly, A. M., Sloma, I., Chiaverelli, R., Moffitt, RA., ... Astsaturov, I. (2020). Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer. Cancer Cell, 38(4), 567-583.e11. https://doi.org/10.1016/j.ccell.2020.08.015

@article{2756f42d61f94c55bf4672498c4ec9e4,

title = "Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer",

abstract = "Oncogenic transformation alters lipid metabolism to sustain tumor growth. We define a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of the rate-limiting enzyme Nsdhl or treatment with cholesterol-lowering statins switches glandular pancreatic carcinomas to a basal (mesenchymal) phenotype in mouse models driven by KrasG12D expression and homozygous Trp53 loss. Consistently, PDACs in patients receiving statins show enhanced mesenchymal features. Mechanistically, statins and NSDHL loss induce SREBP1 activation, which promotes the expression of Tgfb1, enabling epithelial-mesenchymal transition. Evidence from patient samples in this study suggests that activation of transforming growth factor β signaling and epithelial-mesenchymal transition by cholesterol-lowering statins may promote the basal type of PDAC, conferring poor outcomes in patients.",

keywords = "3-Hydroxysteroid Dehydrogenases/genetics, Animals, Atorvastatin/pharmacology, Biosynthetic Pathways/genetics, Carcinoma, Pancreatic Ductal/drug therapy, Cell Differentiation/drug effects, Cell Line, Tumor, Cholesterol, LDL/biosynthesis, Epithelial-Mesenchymal Transition/drug effects, Gene Expression Profiling, Gene Expression Regulation, Neoplastic/drug effects, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology, Kaplan-Meier Estimate, Mice, Inbred C57BL, Mice, Knockout, Pancreatic Neoplasms/drug therapy, Signal Transduction/genetics, Transforming Growth Factor beta/genetics, Xenograft Model Antitumor Assays/methods",

author = "Linara Gabitova-Cornell and Aizhan Surumbayeva and Suraj Peri and Janusz Franco-Barraza and Diana Restifo and N Weitz and Charline Ogier and AR Goldman and Hartman, {Tiffiney R.} and R. Francescone and Y Tan and Emmanuelle Nicolas and N. Shah and Elizabeth Handorf and Kathy Cai and O'Reilly, {Alana M.} and I Sloma and Rachel Chiaverelli and RA Moffitt and V Khazak and Fang, {Carolyn Y.} and Golemis, {Erica A.} and Edna Cukierman and Igor Astsaturov",

year = "2020",

month = oct,

day = "12",

doi = "10.1016/j.ccell.2020.08.015",

language = "English",

volume = "38",

pages = "567--583.e11",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "4",

}

Gabitova-Cornell, L, Surumbayeva, A, Peri, S, Franco-Barraza, J, Restifo, D, Weitz, N, Ogier, C, Goldman, AR, Hartman, TR, Francescone, R, Tan, Y, Nicolas, E, Shah, N, Handorf, E, Cai, K , O'Reilly, AM, Sloma, I, Chiaverelli, R, Moffitt, RA, Khazak, V, Fang, CY , Golemis, EA , Cukierman, E & Astsaturov, I 2020, 'Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer', Cancer Cell, vol. 38, no. 4, pp. 567-583.e11. https://doi.org/10.1016/j.ccell.2020.08.015

TY - JOUR

T1 - Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer

AU - Gabitova-Cornell, Linara

AU - Surumbayeva, Aizhan

AU - Peri, Suraj

AU - Franco-Barraza, Janusz

AU - Restifo, Diana

AU - Weitz, N

AU - Ogier, Charline

AU - Goldman, AR

AU - Hartman, Tiffiney R.

AU - Francescone, R.

AU - Tan, Y

AU - Nicolas, Emmanuelle

AU - Shah, N.

AU - Handorf, Elizabeth

AU - Cai, Kathy

AU - O'Reilly, Alana M.

AU - Sloma, I

AU - Chiaverelli, Rachel

AU - Moffitt, RA

AU - Khazak, V

AU - Fang, Carolyn Y.

AU - Golemis, Erica A.

AU - Cukierman, Edna

AU - Astsaturov, Igor

PY - 2020/10/12

Y1 - 2020/10/12

N2 - Oncogenic transformation alters lipid metabolism to sustain tumor growth. We define a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of the rate-limiting enzyme Nsdhl or treatment with cholesterol-lowering statins switches glandular pancreatic carcinomas to a basal (mesenchymal) phenotype in mouse models driven by KrasG12D expression and homozygous Trp53 loss. Consistently, PDACs in patients receiving statins show enhanced mesenchymal features. Mechanistically, statins and NSDHL loss induce SREBP1 activation, which promotes the expression of Tgfb1, enabling epithelial-mesenchymal transition. Evidence from patient samples in this study suggests that activation of transforming growth factor β signaling and epithelial-mesenchymal transition by cholesterol-lowering statins may promote the basal type of PDAC, conferring poor outcomes in patients.

AB - Oncogenic transformation alters lipid metabolism to sustain tumor growth. We define a mechanism by which cholesterol metabolism controls the development and differentiation of pancreatic ductal adenocarcinoma (PDAC). Disruption of distal cholesterol biosynthesis by conditional inactivation of the rate-limiting enzyme Nsdhl or treatment with cholesterol-lowering statins switches glandular pancreatic carcinomas to a basal (mesenchymal) phenotype in mouse models driven by KrasG12D expression and homozygous Trp53 loss. Consistently, PDACs in patients receiving statins show enhanced mesenchymal features. Mechanistically, statins and NSDHL loss induce SREBP1 activation, which promotes the expression of Tgfb1, enabling epithelial-mesenchymal transition. Evidence from patient samples in this study suggests that activation of transforming growth factor β signaling and epithelial-mesenchymal transition by cholesterol-lowering statins may promote the basal type of PDAC, conferring poor outcomes in patients.

KW - 3-Hydroxysteroid Dehydrogenases/genetics

KW - Animals

KW - Atorvastatin/pharmacology

KW - Biosynthetic Pathways/genetics

KW - Carcinoma, Pancreatic Ductal/drug therapy

KW - Cell Differentiation/drug effects

KW - Cell Line, Tumor

KW - Cholesterol, LDL/biosynthesis

KW - Epithelial-Mesenchymal Transition/drug effects

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic/drug effects

KW - Humans

KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology

KW - Kaplan-Meier Estimate

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Pancreatic Neoplasms/drug therapy

KW - Signal Transduction/genetics

KW - Transforming Growth Factor beta/genetics

KW - Xenograft Model Antitumor Assays/methods

UR - http://www.scopus.com/inward/record.url?scp=85092205921&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2020.08.015

DO - 10.1016/j.ccell.2020.08.015

M3 - Article

C2 - 32976774

SN - 1535-6108

VL - 38

SP - 567-583.e11

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Biological Imaging Facility

Biosample Repository Facility

Biostatistics and Bioinformatics Facility

Cite this

Cholesterol Pathway Inhibition Induces TGF-β Signaling to Promote Basal Differentiation in Pancreatic Cancer

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Equipment

Biological Imaging Facility

Biosample Repository Facility

Biostatistics and Bioinformatics Facility

Cite this