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

被引：127

作者：

Gabitova-Cornell, Linara ^{[1
,2
]}

Surumbayeva, Aizhan ^{[1
,2
]}

Peri, Suraj ^{[3
]}

Franco-Barraza, Janusz ^{[2
,4
]}

Restifo, Diana ^{[1
,2
]}

Weitz, Nicole ^{[1
,2
]}

Ogier, Charline ^{[1
,2
]}

Goldman, Aaron R. ^{[5
]}

Hartman, Tiffiney R. ^{[1
]}

Francescone, Ralph ^{[2
,4
]}

Tan, Yinfei ^{[4
]}

Nicolas, Emmanuelle ^{[1
]}

Shah, Neelima ^{[2
,4
]}

Handorf, Elizabeth A. ^{[3
]}

Cai, Kathy Q. ^{[4
]}

O'Reilly, Alana M. ^{[1
]}

Sloma, Ido ^{[6
]}

Chiaverelli, Rachel ^{[6
]}

Moffitt, Richard A. ^{[7
]}

Khazak, Vladimir ^{[8
]}

Fang, Carolyn Y. ^{[9
]}

Golemis, Erica A. ^{[1
]}

Cukierman, Edna ^{[2
,4
]}

Astsaturov, Igor ^{[1
,2
,10
]}

机构：

[1] Fox Chase Canc Ctr, Mol Therapeut Program, 333 Cottman Ave, Philadelphia, PA 19111 USA

[2] Fox Chase Canc Ctr, Marvin & Concetta Greenberg Pancreat Canc Inst, 7701 Burholme Ave, Philadelphia, PA 19111 USA

[3] Fox Chase Canc Ctr, Biostat & Bioinformat Facil, 7701 Burholme Ave, Philadelphia, PA 19111 USA

[4] Fox Chase Canc Ctr, Canc Biol Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA

[5] Wistar Inst Anat & Biol, Prote & Metabol Facil, 3601 Spruce St, Philadelphia, PA 19104 USA

[6] Champ Oncol Inc, Hackensack, NJ USA

[7] Stony Brook Canc Ctr, Dept Biomed Informat, Stony Brook, NY USA

[8] NexusPharma Inc, Philadelphia, PA USA

[9] Fox Chase Canc Ctr, Canc Prevent & Control Program, 7701 Burholme Ave, Philadelphia, PA 19111 USA

[10] Kazan Fed Univ, Kazan, Russia

来源：

CANCER CELL | 2020年 / 38卷 / 04期

关键词：

DUCTAL ADENOCARCINOMA; GENE-EXPRESSION; ACTIVATION; TUMOR; TRANSCRIPTION; SUBTYPES; P53; PHOSPHORYLATION; PROGRESSION; METASTASIS;

D O I：

10.1016/j.ccell.2020.08.015

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 beta signaling and epithelial-mesenchymal transition by cholesterol-lowering statins may promote the basal type of PDAC, conferring poor outcomes in patients.

引用

页码：567 / +

页数：28

共 81 条

[1] Transcriptional control of subtype switching ensures adaptation and growth of pancreatic cancer [J].

Adams, Christina R. ;

Htwe, Htet Htwe ;

Marsh, Timothy ;

Wang, Aprilgate L. ;

Montoya, Megan L. ;

Subbaraj, Lakshmipriya ;

Tward, Aaron D. ;

Bardeesy, Nabeel ;

Perera, Rushika M. .

ELIFE, 2019, 8

[2] Cholesterol and 25-hydroxycholesterol inhibit activation of SREBPs by different mechanisms, both involving SCAP and insigs [J].

Adams, CM ;

Reitz, J ;

De Brabander, JK ;

Feramisco, JD ;

Li, L ;

Brown, MS ;

Goldstein, JL .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (50) :52772-52780

[3] Upholding a role for EMT in pancreatic cancer metastasis [J].

Aiello, Nicole M. ;

Brabletz, Thomas ;

Kang, Yibin ;

Angela Nieto, M. ;

Weinberg, Robert A. ;

Stanger, Ben Z. .

NATURE, 2017, 547 (7661) :E7-E8

[4] HTSeq-a Python']Python framework to work with high-throughput sequencing data [J].

Anders, Simon ;

Pyl, Paul Theodor ;

Huber, Wolfgang .

BIOINFORMATICS, 2015, 31 (02) :166-169

[5] Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial [J].

Aung, Kyaw L. ;

Fischer, Sandra E. ;

Denroche, Robert E. ;

Jang, Gun-Ho ;

Dodd, Anna ;

Creighton, Sean ;

Southwood, Bernadette ;

Liang, Sheng-Ben ;

Chadwick, Dianne ;

Zhang, Amy ;

O'Kane, Grainne M. ;

Albaba, Hamzeh ;

Moura, Shari ;

Grant, Robert C. ;

Miller, Jessica K. ;

Mbabaali, Faridah ;

Pasternack, Danielle ;

Lungu, Ilinca M. ;

Bartlett, John M. S. ;

Ghai, Sangeet ;

Lemire, Mathieu ;

Holter, Spring ;

Connor, Ashton A. ;

Moffitt, Richard A. ;

Yeh, Jen Jen ;

Timms, Lee ;

Krzyzanowski, Paul M. ;

Dhani, Neesha ;

Hedley, David ;

Notta, Faiyaz ;

Wilson, Julie M. ;

Moore, Malcolm J. ;

Gallinger, Steven ;

Knox, Jennifer J. .

CLINICAL CANCER RESEARCH, 2018, 24 (06) :1344-1354

[6] Genomic analyses identify molecular subtypes of pancreatic cancer [J].

Bailey, Peter ;

Chang, David K. ;

Nones, Katia ;

Johns, Amber L. ;

Patch, Ann-Marie ;

Gingras, Marie-Claude ;

Miller, David K. ;

Christ, Angelika N. ;

Bruxner, Tim J. C. ;

Quinn, Michael C. ;

Nourse, Craig ;

Murtaugh, L. Charles ;

Harliwong, Ivon ;

Idrisoglu, Senel ;

Manning, Suzanne ;

Nourbakhsh, Ehsan ;

Wani, Shivangi ;

Fink, Lynn ;

Holmes, Oliver ;

Chin, Vencssa ;

Anderson, Matthew J. ;

Kazakoff, Stephen ;

Leonard, Conrad ;

Newell, Felicity ;

Waddell, Nick ;

Wood, Scott ;

Xu, Qinying ;

Wilson, Peter J. ;

Cloonan, Nicole ;

Kassahn, Karin S. ;

Taylor, Darrin ;

Quek, Kelly ;

Robertson, Alan ;

Pantano, Lorena ;

Mincarelli, Laura ;

Sanchez, Luis N. ;

Evers, Lisa ;

Wu, Jianmin ;

Pinese, Mark ;

Cowley, Mark J. ;

Jones, Marc D. ;

Colvin, Emily K. ;

Nagrial, Adnan M. ;

Humphrey, Emily S. ;

Chantrill, Lorraine A. ;

Mawson, Amanda ;

Humphris, Jeremy ;

Chou, Angela ;

Pajic, Marina ;

Scarlett, Christopher J. .

NATURE, 2016, 531 (7592) :47-+

[7] The relationship between the use of statins and mortality, severity, and pancreatic cancer in Danish patients with chronic pancreatitis [J].

Bang, Ulrich C. ;

Watanabe, Tomohiro ;

Bendtsen, Flemming .

EUROPEAN JOURNAL OF GASTROENTEROLOGY & HEPATOLOGY, 2018, 30 (03) :346-351

[8] Both p16Ink4a and the p19Arf-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse [J].

Bardeesy, N ;

Aguirre, AJ ;

Chu, GC ;

Cheng, KH ;

Lopez, LV ;

Hezel, AF ;

Feng, B ;

Brennan, C ;

Weissleder, R ;

Mahmood, U ;

Hanahan, D ;

Redston, MS ;

Chin, L ;

DePinho, RA .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2006, 103 (15) :5947-5952

[9] IL1-Induced JAK/STAT Signaling Is Antagonized by TGFβ to Shape CAF Heterogeneity in Pancreatic Ductal Adenocarcinoma [J].

Biffi, Giulia ;

Oni, Tobiloba E. ;

Spielman, Benjamin ;

Hao, Yuan ;

Elyada, Ela ;

Park, Youngkyu ;

Preall, Jonathan ;

Tuveson, David A. .

CANCER DISCOVERY, 2019, 9 (02) :282-301

[10]

BROWN MS, 1978, J BIOL CHEM, V253, P1121

← 1 2 3 4 5 6 7 8 9 →