Three-dimensional visualization of cleared human pancreas cancer reveals that sustained epithelial-to-mesenchymal transition is not required for venous invasion

Seung Mo Hong, Dong Jun Jung, Ashley Kiemen, Matthias M. Gaida, Tadashi Yoshizawa, Alicia M. Braxton, Michaël Noë, Gemma Lionheart, Kiyoko Oshima, Elizabeth D. Thompson, Richard Burkhart, Pei Hsun Wu, Denis Wirtz, Ralph H. Hruban, Laura D. Wood

Research output: Contribution to journalArticle

Abstract

Venous invasion is three times more common in pancreatic cancer than it is in other major cancers of the gastrointestinal tract, and venous invasion may explain why pancreatic cancer is so deadly. To characterize the patterns of venous invasion in pancreatic cancer, 52 thick slabs (up to 5 mm) of tissue were harvested from 52 surgically resected human ductal adenocarcinomas, cleared with a modified iDISCO method, and labeled with fluorescent-conjugated antibodies to cytokeratin 19, desmin, CD31, p53 and/or e-cadherin. Labeled three-dimensional (3D) pancreas cancer tissues were visualized with confocal laser scanning or light sheet microscopy. Multiple foci of venous and even arterial invasion were visualized. Venous invasion was detected more often in 3D (88%, 30/34 cases) than in conventional 2D slide evaluation (75%, 25/34 cases, P < 0.001). 3D visualization revealed pancreatic cancer cells crossing the walls of veins at multiple points, often at points where preexisting capillary structures bridge the blood vessels. The neoplastic cells often retained a ductal morphology (cohesive cells forming tubes) as they progressed from a stromal to intravenous location. Although immunolabeling with antibodies to e-cadherin revealed focal loss of expression at the leading edges of the cancers, the neoplastic cells within veins expressed e-cadherin and formed well-oriented glands. We conclude that venous invasion is almost universal in pancreatic cancer, suggesting that even surgically resectable PDAC has access to the venous spaces and thus the ability to disseminate widely. Furthermore, we observe that sustained epithelial–mesenchymal transition is not required for venous invasion in pancreatic cancer.

Original languageEnglish (US)
JournalModern Pathology
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Epithelial-Mesenchymal Transition
Pancreatic Neoplasms
Cadherins
Veins
Keratin-19
Gastrointestinal Neoplasms
Desmin
Antibodies
Cell Wall
Blood Vessels
Microscopy
Adenocarcinoma
Lasers
Light
Neoplasms

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Three-dimensional visualization of cleared human pancreas cancer reveals that sustained epithelial-to-mesenchymal transition is not required for venous invasion. / Hong, Seung Mo; Jung, Dong Jun; Kiemen, Ashley; Gaida, Matthias M.; Yoshizawa, Tadashi; Braxton, Alicia M.; Noë, Michaël; Lionheart, Gemma; Oshima, Kiyoko; Thompson, Elizabeth D.; Burkhart, Richard; Wu, Pei Hsun; Wirtz, Denis; Hruban, Ralph H.; Wood, Laura D.

In: Modern Pathology, 01.01.2019.

Research output: Contribution to journalArticle

@article{a8cbfba0bfac4f678d4a7bddb60fe384,
title = "Three-dimensional visualization of cleared human pancreas cancer reveals that sustained epithelial-to-mesenchymal transition is not required for venous invasion",
abstract = "Venous invasion is three times more common in pancreatic cancer than it is in other major cancers of the gastrointestinal tract, and venous invasion may explain why pancreatic cancer is so deadly. To characterize the patterns of venous invasion in pancreatic cancer, 52 thick slabs (up to 5 mm) of tissue were harvested from 52 surgically resected human ductal adenocarcinomas, cleared with a modified iDISCO method, and labeled with fluorescent-conjugated antibodies to cytokeratin 19, desmin, CD31, p53 and/or e-cadherin. Labeled three-dimensional (3D) pancreas cancer tissues were visualized with confocal laser scanning or light sheet microscopy. Multiple foci of venous and even arterial invasion were visualized. Venous invasion was detected more often in 3D (88{\%}, 30/34 cases) than in conventional 2D slide evaluation (75{\%}, 25/34 cases, P < 0.001). 3D visualization revealed pancreatic cancer cells crossing the walls of veins at multiple points, often at points where preexisting capillary structures bridge the blood vessels. The neoplastic cells often retained a ductal morphology (cohesive cells forming tubes) as they progressed from a stromal to intravenous location. Although immunolabeling with antibodies to e-cadherin revealed focal loss of expression at the leading edges of the cancers, the neoplastic cells within veins expressed e-cadherin and formed well-oriented glands. We conclude that venous invasion is almost universal in pancreatic cancer, suggesting that even surgically resectable PDAC has access to the venous spaces and thus the ability to disseminate widely. Furthermore, we observe that sustained epithelial–mesenchymal transition is not required for venous invasion in pancreatic cancer.",
author = "Hong, {Seung Mo} and Jung, {Dong Jun} and Ashley Kiemen and Gaida, {Matthias M.} and Tadashi Yoshizawa and Braxton, {Alicia M.} and Micha{\"e}l No{\"e} and Gemma Lionheart and Kiyoko Oshima and Thompson, {Elizabeth D.} and Richard Burkhart and Wu, {Pei Hsun} and Denis Wirtz and Hruban, {Ralph H.} and Wood, {Laura D.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41379-019-0409-3",
language = "English (US)",
journal = "Modern Pathology",
issn = "0893-3952",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Three-dimensional visualization of cleared human pancreas cancer reveals that sustained epithelial-to-mesenchymal transition is not required for venous invasion

AU - Hong, Seung Mo

AU - Jung, Dong Jun

AU - Kiemen, Ashley

AU - Gaida, Matthias M.

AU - Yoshizawa, Tadashi

AU - Braxton, Alicia M.

AU - Noë, Michaël

AU - Lionheart, Gemma

AU - Oshima, Kiyoko

AU - Thompson, Elizabeth D.

AU - Burkhart, Richard

AU - Wu, Pei Hsun

AU - Wirtz, Denis

AU - Hruban, Ralph H.

AU - Wood, Laura D.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Venous invasion is three times more common in pancreatic cancer than it is in other major cancers of the gastrointestinal tract, and venous invasion may explain why pancreatic cancer is so deadly. To characterize the patterns of venous invasion in pancreatic cancer, 52 thick slabs (up to 5 mm) of tissue were harvested from 52 surgically resected human ductal adenocarcinomas, cleared with a modified iDISCO method, and labeled with fluorescent-conjugated antibodies to cytokeratin 19, desmin, CD31, p53 and/or e-cadherin. Labeled three-dimensional (3D) pancreas cancer tissues were visualized with confocal laser scanning or light sheet microscopy. Multiple foci of venous and even arterial invasion were visualized. Venous invasion was detected more often in 3D (88%, 30/34 cases) than in conventional 2D slide evaluation (75%, 25/34 cases, P < 0.001). 3D visualization revealed pancreatic cancer cells crossing the walls of veins at multiple points, often at points where preexisting capillary structures bridge the blood vessels. The neoplastic cells often retained a ductal morphology (cohesive cells forming tubes) as they progressed from a stromal to intravenous location. Although immunolabeling with antibodies to e-cadherin revealed focal loss of expression at the leading edges of the cancers, the neoplastic cells within veins expressed e-cadherin and formed well-oriented glands. We conclude that venous invasion is almost universal in pancreatic cancer, suggesting that even surgically resectable PDAC has access to the venous spaces and thus the ability to disseminate widely. Furthermore, we observe that sustained epithelial–mesenchymal transition is not required for venous invasion in pancreatic cancer.

AB - Venous invasion is three times more common in pancreatic cancer than it is in other major cancers of the gastrointestinal tract, and venous invasion may explain why pancreatic cancer is so deadly. To characterize the patterns of venous invasion in pancreatic cancer, 52 thick slabs (up to 5 mm) of tissue were harvested from 52 surgically resected human ductal adenocarcinomas, cleared with a modified iDISCO method, and labeled with fluorescent-conjugated antibodies to cytokeratin 19, desmin, CD31, p53 and/or e-cadherin. Labeled three-dimensional (3D) pancreas cancer tissues were visualized with confocal laser scanning or light sheet microscopy. Multiple foci of venous and even arterial invasion were visualized. Venous invasion was detected more often in 3D (88%, 30/34 cases) than in conventional 2D slide evaluation (75%, 25/34 cases, P < 0.001). 3D visualization revealed pancreatic cancer cells crossing the walls of veins at multiple points, often at points where preexisting capillary structures bridge the blood vessels. The neoplastic cells often retained a ductal morphology (cohesive cells forming tubes) as they progressed from a stromal to intravenous location. Although immunolabeling with antibodies to e-cadherin revealed focal loss of expression at the leading edges of the cancers, the neoplastic cells within veins expressed e-cadherin and formed well-oriented glands. We conclude that venous invasion is almost universal in pancreatic cancer, suggesting that even surgically resectable PDAC has access to the venous spaces and thus the ability to disseminate widely. Furthermore, we observe that sustained epithelial–mesenchymal transition is not required for venous invasion in pancreatic cancer.

UR - http://www.scopus.com/inward/record.url?scp=85074827773&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074827773&partnerID=8YFLogxK

U2 - 10.1038/s41379-019-0409-3

DO - 10.1038/s41379-019-0409-3

M3 - Article

C2 - 31700162

AN - SCOPUS:85074827773

JO - Modern Pathology

JF - Modern Pathology

SN - 0893-3952

ER -