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

Sergio Kaiser, Young Kyu Park, Jeffrey L. Franklin, Richard B. Halberg, Ming Yu, Walter J. Jessen, Johannes Freudenberg, Xiaodi Chen, Kevin Haigis, Anil G. Jegga, Sue Kong, Bhuvaneswari Sakthivel, Huan Xu, Timothy Reichling, Mohammad Azhar, Gregory P. Boivin, Reade B. Roberts, Anika C. Bissahoyo, Fausto Gonzales, Greg C. BloomSteven Eschrich, Scott L. Carter, Jeremy E. Aronow, John Kleimeyer, Michael Kleimeyer, Vivek Ramaswamy, Stephen H. Settle, Braden Boone, Shawn Levy, Jonathan M. Graff, Thomas C Doetschman, Joanna Groden, William F. Dove, David W. Threadgill, Timothy J. Yeatman, Robert J. Coffey, Bruce J. Aronow

Research output: Contribution to journalArticle

210 Citations (Scopus)

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.

Original languageEnglish (US)
Article numberR131
JournalGenome Biology
Volume8
Issue number7
DOIs
StatePublished - Jul 5 2007

Fingerprint

embryonic development
colorectal neoplasms
tumor
Colonic Neoplasms
colon
Embryonic Development
cancer
Colon
neoplasms
mice
gene expression
Colorectal Neoplasms
Neoplasms
Gene Expression
carcinogenesis
animal models
Carcinogenesis
suppressor genes
therapeutics
Suppressor Genes

ASJC Scopus subject areas

  • Genetics
  • Cell Biology
  • Ecology, Evolution, Behavior and Systematics

Cite this

Kaiser, S., Park, Y. K., Franklin, J. L., Halberg, R. B., Yu, M., Jessen, W. J., ... Aronow, B. J. (2007). Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer. Genome Biology, 8(7), [R131]. https://doi.org/10.1186/gb-2007-8-7-r131

Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer. / 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 C; Groden, Joanna; Dove, William F.; Threadgill, David W.; Yeatman, Timothy J.; Coffey, Robert J.; Aronow, Bruce J.

In: Genome Biology, Vol. 8, No. 7, R131, 05.07.2007.

Research output: Contribution to journalArticle

Kaiser, S, Park, YK, Franklin, JL, Halberg, RB, Yu, M, Jessen, WJ, Freudenberg, J, Chen, X, Haigis, K, Jegga, AG, Kong, S, Sakthivel, B, Xu, H, Reichling, T, Azhar, M, Boivin, GP, Roberts, RB, Bissahoyo, AC, Gonzales, F, Bloom, GC, Eschrich, S, Carter, SL, Aronow, JE, Kleimeyer, J, Kleimeyer, M, Ramaswamy, V, Settle, SH, Boone, B, Levy, S, Graff, JM, Doetschman, TC, Groden, J, Dove, WF, Threadgill, DW, Yeatman, TJ, Coffey, RJ & Aronow, BJ 2007, 'Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer', Genome Biology, vol. 8, no. 7, R131. https://doi.org/10.1186/gb-2007-8-7-r131
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 C ; Groden, Joanna ; Dove, William F. ; Threadgill, David W. ; Yeatman, Timothy J. ; Coffey, Robert J. ; Aronow, Bruce J. / Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer. In: Genome Biology. 2007 ; Vol. 8, No. 7.
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title = "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.",
author = "Sergio Kaiser and Park, {Young Kyu} and Franklin, {Jeffrey L.} and Halberg, {Richard B.} and Ming Yu and Jessen, {Walter J.} and Johannes Freudenberg and Xiaodi Chen and Kevin Haigis and Jegga, {Anil G.} and Sue Kong and Bhuvaneswari Sakthivel and Huan Xu and Timothy Reichling and Mohammad Azhar and Boivin, {Gregory P.} and Roberts, {Reade B.} and Bissahoyo, {Anika C.} and Fausto Gonzales and Bloom, {Greg C.} and Steven Eschrich and Carter, {Scott L.} and Aronow, {Jeremy E.} and John Kleimeyer and Michael Kleimeyer and Vivek Ramaswamy and Settle, {Stephen H.} and Braden Boone and Shawn Levy and Graff, {Jonathan M.} and Doetschman, {Thomas C} and Joanna Groden and Dove, {William F.} and Threadgill, {David W.} and Yeatman, {Timothy J.} and Coffey, {Robert J.} and Aronow, {Bruce J.}",
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TY - JOUR

T1 - Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer

AU - Kaiser, Sergio

AU - Park, Young Kyu

AU - Franklin, Jeffrey L.

AU - Halberg, Richard B.

AU - Yu, Ming

AU - Jessen, Walter J.

AU - Freudenberg, Johannes

AU - Chen, Xiaodi

AU - Haigis, Kevin

AU - Jegga, Anil G.

AU - Kong, Sue

AU - Sakthivel, Bhuvaneswari

AU - Xu, Huan

AU - Reichling, Timothy

AU - Azhar, Mohammad

AU - Boivin, Gregory P.

AU - Roberts, Reade B.

AU - Bissahoyo, Anika C.

AU - Gonzales, Fausto

AU - Bloom, Greg C.

AU - Eschrich, Steven

AU - Carter, Scott L.

AU - Aronow, Jeremy E.

AU - Kleimeyer, John

AU - Kleimeyer, Michael

AU - Ramaswamy, Vivek

AU - Settle, Stephen H.

AU - Boone, Braden

AU - Levy, Shawn

AU - Graff, Jonathan M.

AU - Doetschman, Thomas C

AU - Groden, Joanna

AU - Dove, William F.

AU - Threadgill, David W.

AU - Yeatman, Timothy J.

AU - Coffey, Robert J.

AU - Aronow, Bruce J.

PY - 2007/7/5

Y1 - 2007/7/5

N2 - 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.

AB - 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.

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