TY - JOUR
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.
N1 - Funding Information:
We are grateful to Laura Libby, Emily M. Silva, and Danielle Bestoso for mouse colony care and administrative support. This work was supported by American-Italian Cancer Foundation Post-Doctoral Research Fellowship (to M.L.), Hirshberg Foundation seed grant (M.L), Tosteson and Fund for Medical Discovery Fellowship (to M.L.), the Burroughs Wellcome Fund (to D.T.T. and M.N.R.), the NSF ( PHY-1549535 to D.T.T.), SU2C and Lustgarten Foundation (to D.T.T.), the V Foundation (to M.R.), Affymetrix, Inc. (to D.T.T., K.S.A., N.D., M.N.R., and V.D.), NIH ( T32GM007753 to R.Y.E.; U01 CA215798 to W.H.; 2R01CA129933 and 2U01EB012493 to D.A.H.; U01CA214297 to D.A.H. and S.M.), the Warshaw Institute for Pancreatic Cancer Research (to D.T.T. and M.L.), the Verville Family Pancreatic Cancer Research Fund (to D.T.T.), ESSCO Breast Cancer Research (to S.M.), the Breast Cancer Research Foundation (to D.A.H.), Howard Hughes Medical Institute (to D.A.H.), the National Foundation for Cancer Research (to D.A.H.), and NCI ( U01CA215798 to W.H.).
Funding Information:
We are grateful to Laura Libby, Emily M. Silva, and Danielle Bestoso for mouse colony care and administrative support. This work was supported by American-Italian Cancer Foundation Post-Doctoral Research Fellowship (to M.L.), Hirshberg Foundation seed grant (M.L), Tosteson and Fund for Medical Discovery Fellowship (to M.L.), the Burroughs Wellcome Fund (to D.T.T. and M.N.R.), the NSF (PHY-1549535 to D.T.T.), SU2C and Lustgarten Foundation (to D.T.T.), the V Foundation (to M.R.), Affymetrix, Inc. (to D.T.T. K.S.A. N.D. M.N.R. and V.D.), NIH (T32GM007753 to R.Y.E.; U01 CA215798 to W.H.; 2R01CA129933 and 2U01EB012493 to D.A.H.; U01CA214297 to D.A.H. and S.M.), the Warshaw Institute for Pancreatic Cancer Research (to D.T.T. and M.L.), the Verville Family Pancreatic Cancer Research Fund (to D.T.T.), ESSCO Breast Cancer Research (to S.M.), the Breast Cancer Research Foundation (to D.A.H.), Howard Hughes Medical Institute (to D.A.H.), the National Foundation for Cancer Research (to D.A.H.), and NCI (U01CA215798 to W.H.). Conceptualization, M.L. M.A. and D.T.T.; Methodology, M.L. S.S. J.M.-L. L.T.N. and M.J.A.; Software, S.S. A.L. V.T. R.M. M.S.L. and M.J.A.; Formal Analysis, M.L. S.S. J.M.-L. L.T.N. M.J.A. and D.T.T.; Investigation, M.L. S.S. J.M.-L. L.T.N. S.M. M.D.P. R.Y.E. M.K. A.S.K. A.L. N.V.J. J.W.F. J.P. J.K. N.D. K.S.A. M.R. E.H. A.N. E.T. N.K.C.M. K.D.V. C.N.Y. F.M. M.B. J.P.F. L.J.D. K.X. R.D. M.C. F.B. U.F.W. O.S. M.J.A. and D.T.T.; Resources, A.L. M.N.R. V.D. C.B. S.M. D.A.H. C.F.-D.-C. C.R.F. and W.H.; Writing – Original Draft, M.L. M.J.A. and D.T.T.; Writing – Review & Editing, M.L. W.H. J.M.-L. L.T.N. M.J.A. and D.T.T.; Visualization, M.L. S.S. J.M.-L. L.T.N. and M.J.A.; Supervision, M.J.A. and D.T.T.; Project Administration, M.J.A. and D.T.T.; Funding Acquisition, M.J.A. and D.T.T. D.T.T. has received consulting fees from Merrimack Pharmaceuticals, Ventana Roche, and EMD Millipore Sigma, which are not related to this work. D.T.T. is a founder and has equity in PanTher Therapeutics, which is not related to this work. D.T.T. V.D. and M.N.R. have a sponsored research agreement with ACD-Biotechne and previously with Affymetrix. M.J.A has received consulting income from SynapDx, BlueBird Bio, Fulcrum Therapeutics, Leap Therapeutics, NextGenJane, Progenity, Inc. and Third Rock Ventures, not related to this work. M.J.A. has financial interests in Monitor Biotechnologies (formerly known as Beacon Genomics), not related to this work. M.L. has received consulting fees from Merrimack Pharmaceuticals not related to this work. J.W.F is a paid consultant with Foundation Medicine, not related to this work.
Publisher Copyright:
© 2019 Elsevier Inc.
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
UR - http://www.scopus.com/inward/record.url?scp=85067683716&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067683716&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2019.05.012
DO - 10.1016/j.cell.2019.05.012
M3 - Article
C2 - 31155233
AN - SCOPUS:85067683716
SN - 0092-8674
VL - 178
SP - 160-175.e27
JO - Cell
JF - Cell
IS - 1
ER -