Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer

Matteo Ligorio; Srinjoy Sil; Jose Malagon-Lopez; Linda T. Nieman; Sandra Misale; Mauro Di Pilato; Richard Y. Ebright; Murat N. Karabacak; Anupriya S. Kulkarni; Ann Liu; Nicole Vincent Jordan; Joseph W. Franses; Julia Philipp; Johannes Kreuzer; Niyati Desai; Kshitij S. Arora; Mihir Rajurkar; Elad Horwitz; Azfar Neyaz; Eric Tai; Neelima K.C. Magnus; Kevin D. Vo; Chittampalli N. Yashaswini; Francesco Marangoni; Myriam Boukhali; Jackson P. Fatherree; Leah J. Damon; Kristina Xega; Rushil Desai; Melissa Choz; Francesca Bersani; Adam Langenbucher; Vishal Thapar; Robert Morris; Ulrich F. Wellner; Oliver Schilling; Michael S. Lawrence; Andrew S. Liss; Miguel N. Rivera; Vikram Deshpande; Cyril H. Benes; Shyamala Maheswaran; Daniel A. Haber; Carlos Fernandez-Del-Castillo; Cristina R. Ferrone; Wilhelm Haas; Martin J. Aryee; David T. Ting

doi:10.1016/j.cell.2019.05.012

Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer

Matteo Ligorio, Srinjoy Sil, Jose Malagon-Lopez, Linda T. Nieman, Sandra Misale, Mauro Di Pilato, Richard Y. Ebright, Murat N. Karabacak, Anupriya S. Kulkarni, Ann Liu, Nicole Vincent Jordan, Joseph W. Franses, Julia Philipp, Johannes Kreuzer, Niyati Desai, Kshitij S. Arora, Mihir Rajurkar, Elad Horwitz, Azfar Neyaz, Eric TaiNeelima K.C. Magnus, Kevin D. Vo, Chittampalli N. Yashaswini, Francesco Marangoni, Myriam Boukhali, Jackson P. Fatherree, Leah J. Damon, Kristina Xega, Rushil Desai, Melissa Choz, Francesca Bersani, Adam Langenbucher, Vishal Thapar, Robert Morris, Ulrich F. Wellner, Oliver Schilling, Michael S. Lawrence, Andrew S. Liss, Miguel N. Rivera, Vikram Deshpande, Cyril H. Benes, Shyamala Maheswaran, Daniel A. Haber, Carlos Fernandez-Del-Castillo, Cristina R. Ferrone, Wilhelm Haas, Martin J. Aryee, David T. Ting

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

345 Scopus citations

Abstract

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. Clinical outcomes for pancreatic cancer are impacted by intra-tumoral tissue architecture as defined by single-cell analyses and high content digital imaging.

Original language	English (US)
Pages (from-to)	160-175.e27
Journal	Cell
Volume	178
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2019.05.012
State	Published - Jun 27 2019
Externally published	Yes

Keywords

mass spectrometry
pancreatic cancer
pancreatic ductal adenocarcinoma
single cell RNA-sequencing
single cell spatial analysis
stromal microenvironment
tumor architecture

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2019.05.012

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Ligorio, M., Sil, S., Malagon-Lopez, J., Nieman, L. T., Misale, S., Di Pilato, M., Ebright, R. Y., Karabacak, M. N., Kulkarni, A. S., Liu, A., Vincent Jordan, N., Franses, J. W., Philipp, J., Kreuzer, J., Desai, N., Arora, K. S., Rajurkar, M., Horwitz, E., Neyaz, A., ... Ting, D. T. (2019). Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer. Cell, 178(1), 160-175.e27. https://doi.org/10.1016/j.cell.2019.05.012

Ligorio, M, Sil, S, Malagon-Lopez, J, Nieman, LT, Misale, S, Di Pilato, M, Ebright, RY, Karabacak, MN, Kulkarni, AS, Liu, A, Vincent Jordan, N, Franses, JW, Philipp, J, Kreuzer, J, Desai, N, Arora, KS, Rajurkar, M, Horwitz, E, Neyaz, A, Tai, E, Magnus, NKC, Vo, KD, Yashaswini, CN, Marangoni, F, Boukhali, M, Fatherree, JP, Damon, LJ, Xega, K, Desai, R, Choz, M, Bersani, F, Langenbucher, A, Thapar, V, Morris, R, Wellner, UF, Schilling, O, Lawrence, MS, Liss, AS, Rivera, MN, Deshpande, V, Benes, CH, Maheswaran, S, Haber, DA, Fernandez-Del-Castillo, C, Ferrone, CR, Haas, W, Aryee, MJ & Ting, DT 2019, 'Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer', Cell, vol. 178, no. 1, pp. 160-175.e27. https://doi.org/10.1016/j.cell.2019.05.012

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title = "Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer",

abstract = "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. Clinical outcomes for pancreatic cancer are impacted by intra-tumoral tissue architecture as defined by single-cell analyses and high content digital imaging.",

keywords = "mass spectrometry, pancreatic cancer, pancreatic ductal adenocarcinoma, single cell RNA-sequencing, single cell spatial analysis, stromal microenvironment, tumor architecture",

author = "Matteo Ligorio and Srinjoy Sil and Jose Malagon-Lopez and Nieman, {Linda T.} and Sandra Misale and {Di Pilato}, Mauro and Ebright, {Richard Y.} and Karabacak, {Murat N.} and Kulkarni, {Anupriya S.} and Ann Liu and {Vincent Jordan}, Nicole and Franses, {Joseph W.} and Julia Philipp and Johannes Kreuzer and Niyati Desai and Arora, {Kshitij S.} and Mihir Rajurkar and Elad Horwitz and Azfar Neyaz and Eric Tai and Magnus, {Neelima K.C.} and Vo, {Kevin D.} and Yashaswini, {Chittampalli N.} and Francesco Marangoni and Myriam Boukhali and Fatherree, {Jackson P.} and Damon, {Leah J.} and Kristina Xega and Rushil Desai and Melissa Choz and Francesca Bersani and Adam Langenbucher and Vishal Thapar and Robert Morris and Wellner, {Ulrich F.} and Oliver Schilling and Lawrence, {Michael S.} and Liss, {Andrew S.} and Rivera, {Miguel N.} and Vikram Deshpande and Benes, {Cyril H.} and Shyamala Maheswaran and Haber, {Daniel A.} and Carlos Fernandez-Del-Castillo and Ferrone, {Cristina R.} and Wilhelm Haas and Aryee, {Martin J.} and Ting, {David T.}",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = jun,

day = "27",

doi = "10.1016/j.cell.2019.05.012",

language = "English (US)",

volume = "178",

pages = "160--175.e27",

journal = "Cell",

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T1 - Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer

AU - Ligorio, Matteo

AU - Sil, Srinjoy

AU - Malagon-Lopez, Jose

AU - Nieman, Linda T.

AU - Misale, Sandra

AU - Di Pilato, Mauro

AU - Ebright, Richard Y.

AU - Karabacak, Murat N.

AU - Kulkarni, Anupriya S.

AU - Liu, Ann

AU - Vincent Jordan, Nicole

AU - Franses, Joseph W.

AU - Philipp, Julia

AU - Kreuzer, Johannes

AU - Desai, Niyati

AU - Arora, Kshitij S.

AU - Rajurkar, Mihir

AU - Horwitz, Elad

AU - Neyaz, Azfar

AU - Tai, Eric

AU - Magnus, Neelima K.C.

AU - Vo, Kevin D.

AU - Yashaswini, Chittampalli N.

AU - Marangoni, Francesco

AU - Boukhali, Myriam

AU - Fatherree, Jackson P.

AU - Damon, Leah J.

AU - Xega, Kristina

AU - Desai, Rushil

AU - Choz, Melissa

AU - Bersani, Francesca

AU - Langenbucher, Adam

AU - Thapar, Vishal

AU - Morris, Robert

AU - Wellner, Ulrich F.

AU - Schilling, Oliver

AU - Lawrence, Michael S.

AU - Liss, Andrew S.

AU - Rivera, Miguel N.

AU - Deshpande, Vikram

AU - Benes, Cyril H.

AU - Maheswaran, Shyamala

AU - Haber, Daniel A.

AU - Fernandez-Del-Castillo, Carlos

AU - Ferrone, Cristina R.

AU - Haas, Wilhelm

AU - Aryee, Martin J.

AU - Ting, David T.

PY - 2019/6/27

Y1 - 2019/6/27

N2 - 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. Clinical outcomes for pancreatic cancer are impacted by intra-tumoral tissue architecture as defined by single-cell analyses and high content digital imaging.

AB - 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. Clinical outcomes for pancreatic cancer are impacted by intra-tumoral tissue architecture as defined by single-cell analyses and high content digital imaging.

KW - mass spectrometry

KW - pancreatic cancer

KW - pancreatic ductal adenocarcinoma

KW - single cell RNA-sequencing

KW - single cell spatial analysis

KW - stromal microenvironment

KW - tumor architecture

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DO - 10.1016/j.cell.2019.05.012

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AN - SCOPUS:85067683716

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VL - 178

SP - 160-175.e27

JO - Cell

JF - Cell

IS - 1

ER -

Stromal Microenvironment Shapes the Intratumoral Architecture of Pancreatic Cancer

Abstract

Keywords

ASJC Scopus subject areas

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