Colon tumors from four independent mouse models and 100 human colorectal cancers all exhibited striking recapitulation of embryonic colon gene expression from embryonic days 13.5-18.5

A Bissahoyo

AG Jegga

AM Lamhonwah

Anika C Bissahoyo

Anil G Jegga

AP Zbar

AR Moser

AT Kho

Bhuvaneswari Sakthivel

BJ Warner

Braden Boone

Bruce J Aronow

CP Giacomini

CY Logan

D Pinto

David W Threadgill

DH Kim

E Batlle

E Sancho

F Kuhnert

Fausto Gonzales

GP Boivin

Greg C Bloom

Gregory P Boivin

Huan Xu

IM Oving

J Helm

JD Watson

Jeffrey L Franklin

Jeremy E Aronow

Joanna Groden

Johannes Freudenberg

John Kleimeyer

Jonathan M Graff

JP Frederick

JP Heath

JP Katz

JS Lee

Kevin Haigis

KJ Livak

KM Haigis

KY Kwong

L Maggio-Price

L Smit

M Hu

M Jenny

M Kruhoffer

M Lepourcelet

M Plebani

M van de Wetering

ME Valk-Lingbeek

Michael Kleimeyer

Ming Yu

MM Taketo

Mohammad Azhar

NM Munoz

NM Sodir

OJ Sansom

P Khatri

P Zhu

Q Yang

R Nusse

RA Cragg

Reade B Roberts

Richard B Halberg

Robert J Coffey

Scott L Carter

Sergio Kaiser

Shawn Levy

SJ Engle

SK Mithani

Stephen H Settle

Steven Eschrich

Sue Kong

T Brabletz

T Byun

T Kaihara

T Reichling

T Reya

TC He

Thomas Doetschman

Timothy J Yeatman

Timothy Reichling

V Korinek

Vivek Ramaswamy

VUMC

W Zeng

Walter J Jessen

William F Dove

WM Abdel-Rahman

WM Grady

XH Feng

Xiaodi Chen

Y Benjamini

Y Zhu

YK Park

Young-Kyu Park

English

PubMed

Ø Langsrud

Crossref

Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer

Abstract Background The expression of carcino-embryonic antigen by colorectal cancer is an example of oncogenic activation of embryonic gene expression. Hypothesizing that oncogenesis-recapitulating-ontogenesis may represent a broad programmatic commitment, we compared gene expression patterns of human colorectal cancers (CRCs) and mouse colon tumor models to those of mouse colon development embryonic days 13.5-18.5. Results We report here that 39 colon tumors from four independent mouse models and 100 human CRCs encompassing all clinical stages shared a striking recapitulation of embryonic colon gene expression. Compared to normal adult colon, all mouse and human tumors over-expressed a large cluster of genes highly enriched for functional association to the control of cell cycle progression, proliferation, and migration, including those encoding MYC, AKT2, PLK1 and SPARC. Mouse tumors positive for nuclear β-catenin shifted the shared embryonic pattern to that of early development. Human and mouse tumors differed from normal embryonic colon by their loss of expression modules enriched for tumor suppressors (EDNRB, HSPE, KIT and LSP1). Human CRC adenocarcinomas lost an additional suppressor module (IGFBP4, MAP4K1, PDGFRA, STAB1 and WNT4). Many human tumor samples also gained expression of a coordinately regulated module associated with advanced malignancy (ABCC1, FOXO3A, LIF, PIK3R1, PRNP, TNC, TIMP3 and VEGF). Conclusion Cross-species, developmental, and multi-model gene expression patterning comparisons provide an integrated and versatile framework for definition of transcriptional programs associated with oncogenesis. This approach also provides a general method for identifying pattern-specific biomarkers and therapeutic targets. This delineation and categorization of developmental and non-developmental activator and suppressor gene modules can thus facilitate the formulation of sophisticated hypotheses to evaluate potential synergistic effects of targeting within- and between-modules for next-generation combinatorial therapeutics and improved mouse models

Kaiser, Sergio

Park, Young-Kyu

Franklin, Jeffrey L

Halberg, Richard B

Yu, Ming

Jessen, Walter J

Freudenberg, Johannes

Chen, Xiaodi

Haigis, Kevin

Jegga, Anil G

Kong, Sue

Sakthivel, Bhuvaneswari

Xu, Huan

Reichling, Timothy

Azhar, Mohammad

Boivin, Gregory P

Roberts, Reade B

Bissahoyo, Anika C

Gonzales, Fausto

Bloom, Greg C

Eschrich, Steven

Carter, Scott L

Aronow, Jeremy E

Kleimeyer, John

Kleimeyer, Michael

Ramaswamy, Vivek

Settle, Stephen H

Boone, Braden

Levy, Shawn

Graff, Jonathan M

Doetschman, Thomas

Groden, Joanna

Dove, William F

Threadgill, David W.

Yeatman, Timothy J

Coffey, Robert J

Aronow, Bruce J

Carolina Digital Repository

Springer - Publisher Connector

BACKGROUND:The expression of carcino-embryonic antigen by colorectal cancer is an example of oncogenic activation of embryonic gene expression. Hypothesizing that oncogenesis-recapitulating-ontogenesis may represent a broad programmatic commitment, we compared gene expression patterns of human colorectal cancers (CRCs) and mouse colon tumor models to those of mouse colon development embryonic days 13.5-18.5.RESULTS:We report here that 39 colon tumors from four independent mouse models and 100 human CRCs encompassing all clinical stages shared a striking recapitulation of embryonic colon gene expression. Compared to normal adult colon, all mouse and human tumors over-expressed a large cluster of genes highly enriched for functional association to the control of cell cycle progression, proliferation, and migration, including those encoding MYC, AKT2, PLK1 and SPARC. Mouse tumors positive for nuclear beta-catenin shifted the shared embryonic pattern to that of early development. Human and mouse tumors differed from normal embryonic colon by their loss of expression modules enriched for tumor suppressors (EDNRB, HSPE, KIT and LSP1). Human CRC adenocarcinomas lost an additional suppressor module (IGFBP4, MAP4K1, PDGFRA, STAB1 and WNT4). Many human tumor samples also gained expression of a coordinately regulated module associated with advanced malignancy (ABCC1, FOXO3A, LIF, PIK3R1, PRNP, TNC, TIMP3 and VEGF).CONCLUSION:Cross-species, developmental, and multi-model gene expression patterning comparisons provide an integrated and versatile framework for definition of transcriptional programs associated with oncogenesis. This approach also provides a general method for identifying pattern-specific biomarkers and therapeutic targets. This delineation and categorization of developmental and non-developmental activator and suppressor gene modules can thus facilitate the formulation of sophisticated hypotheses to evaluate potential synergistic effects of targeting within- and between-modules for next-generation combinatorial therapeutics and improved mouse models.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at repository@u.library.arizona.edu

Franklin, Jeffrey

Halberg, Richard

Jessen, Walter

Jegga, Anil

Boivin, Gregory

Roberts, Reade

Bissahoyo, Anika

Bloom, Greg

Carter, Scott

Aronow, Jeremy

Settle, Stephen

Graff, Jonathan

The University of Arizona

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Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer

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