Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer

被引：469

作者：

Ligorio, Matteo ^{[1
,2
]}

Sil, Srinjoy ^{[1
]}

Malagon-Lopez, Jose ^{[1
,3
]}

Nieman, Linda T. ^{[1
]}

Misale, Sandra ^{[1
]}

Di Pilato, Mauro ^{[5
]}

Ebright, Richard Y. ^{[1
]}

Karabacak, Murat N. ^{[1
,6
,7
]}

Kulkarni, Anupriya S. ^{[1
]}

Liu, Ann ^{[1
]}

Jordan, Nicole Vincent ^{[1
]}

Franses, Joseph W. ^{[1
]}

Philipp, Julia ^{[1
]}

Kreuzer, Johannes ^{[1
]}

Desai, Niyati ^{[1
]}

Arora, Kshitij S. ^{[1
,2
,3
]}

Rajurkar, Mihir ^{[1
]}

Horwitz, Elad ^{[1
]}

Neyaz, Azfar ^{[1
]}

Tai, Eric ^{[1
]}

Magnus, Neelima Kc ^{[1
]}

Vo, Kevin D. ^{[1
]}

Yashaswini, Chittampalli N. ^{[1
]}

Marangoni, Francesco ^{[5
]}

Boukhali, Myriam ^{[1
]}

Fatherree, Jackson P. ^{[1
]}

Damon, Leah J. ^{[1
]}

Xega, Kristina ^{[1
]}

Desai, Rushil ^{[1
]}

Choz, Melissa ^{[1
]}

Bersani, Francesca ^{[1
]}

Langenbucher, Dam ^{[1
]}

Thapar, Vishal ^{[1
,3
]}

Morris, Robert ^{[1
]}

Wellner, Ulrich F. ^{[8
]}

Schilling, Oliver ^{[9
]}

Lawrence, Michael S. ^{[1
]}

Liss, Andrew S. ^{[2
]}

Rivera, Miguel N. ^{[1
,3
]}

Deshpande, Vikram ^{[1
,3
]}

Benes, Cyril H. ^{[1
]}

Maheswaran, Shyamala ^{[1
,2
]}

Haber, Daniel A. ^{[1
,5
,10
]}

Fernandez-Del-Castillo, Carlos ^{[1
,2
]}

Ferrone, Cristina R. ^{[1
,2
]}

Haas, Wilhelm ^{[1
]}

Aryee, Martin J. ^{[1
,3
,11
]}

Ting, David T. ^{[1
,4
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[4] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA

[5] Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA

[6] Massachusetts Gen Hosp, Ctr Engn Med, Boston, MA 02114 USA

[7] Harvard Med Sch, Boston, MA 02114 USA

[8] Clin Surg, UKSH Campus Lubeck, Lubeck, Germany

[9] Univ Med Ctr Freiburg, Inst Pathol, Freiburg, Germany

[10] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[11] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA

来源：

CELL | 2019年 / 178卷 / 01期

关键词：

STELLATE CELLS; PROTEIN-PHOSPHORYLATION; DUCTAL ADENOCARCINOMA; EXPRESSION; FIBROSIS; PATHWAY; TUMOR; CHEMOTHERAPY; FIBROBLASTS; PROTEOMICS;

D O I：

10.1016/j.cell.2019.05.012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Single-cell technologies have described heterogeneity across tissues, but the spatial distribution and forces that drive single-cell phenotypes have not been well defined. Combining single-cell RNA and protein analytics in studying the role of stromal cancer-associated fibroblasts (CAFs) in modulating heterogeneity in pancreatic cancer (pancreatic ductal adenocarcinoma [PDAC]) model systems, we have identified significant single-cell population shifts toward invasive epithelial-to-mesenchymal transition (EMT) and proliferative (PRO) phenotypes linked with mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling. Using high-content digital imaging of RNA in situ hybridization in 195 PDAC tumors, we quantified these EMT and PRO subpopulations in 319,626 individual cancer cells that can be classified within the context of distinct tumor gland "units." Tumor gland typing provided an additional layer of intratumoral heterogeneity that was associated with differences in stromal abundance and clinical outcomes. This demonstrates the impact of the stroma in shaping tumor architecture by altering inherent patterns of tumor glands in human PDAC.

引用

页码：160 / +

页数：43

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