p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia

Sarah P. Short, Jumpei Kondo, Whitney G. Smalley-Freed, Haruna Takeda, Michael R. Dohn, Anne E. Powell, Robert H. Carnahan, Mary K. Washington, Manish Tripathi, D. Michael Payne, Nancy A. Jenkins, Neal G. Copeland, Robert J. Coffey, Albert B. Reynolds

Research output: Contribution to journalArticle

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Abstract

p120-Catenin (p120) functions as a tumor suppressor in intestinal cancer, but the mechanism is unclear. Here, using conditional p120 knockout in Apc-sensitized mouse models of intestinal cancer, we have identified p120 as an “obligatory” haploinsufficient tumor suppressor. Whereas monoallelic loss of p120 was associated with a significant increase in tumor multiplicity, loss of both alleles was never observed in tumors from these mice. Moreover, forced ablation of the second allele did not further enhance tumorigenesis, but instead induced synthetic lethality in combination with Apc loss of heterozygosity. In tumor-derived organoid cultures, elimination of both p120 alleles resulted in caspase-3–dependent apoptosis that was blocked by inhibition of Rho kinase (ROCK). With ROCK inhibition, however, p120-ablated organoids exhibited a branching phenotype and a substantial increase in cell proliferation. Access to data from Sleeping Beauty mutagenesis screens afforded an opportunity to directly assess the tumorigenic impact of p120 haploinsufficiency relative to other candidate drivers. Remarkably, p120 ranked third among the 919 drivers identified. Cofactors α-catenin and epithelial cadherin (E-cadherin) were also among the highest scoring candidates, indicating a mechanism at the level of the intact complex that may play an important role at very early stages of of intestinal tumorigenesis while simultaneously restricting outright loss via synthetic lethality.

Original languageEnglish (US)
Pages (from-to)4462-4476
Number of pages15
JournalJournal of Clinical Investigation
Volume127
Issue number12
DOIs
StatePublished - Dec 1 2017

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Organoids
Intestinal Neoplasms
Alleles
Neoplasms
Carcinogenesis
Haploinsufficiency
Beauty
Catenins
rho-Associated Kinases
Loss of Heterozygosity
Cadherins
Caspases
Mutagenesis
Cell Proliferation
delta catenin
Apoptosis
Phenotype
Synthetic Lethal Mutations
Inhibition (Psychology)

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Short, S. P., Kondo, J., Smalley-Freed, W. G., Takeda, H., Dohn, M. R., Powell, A. E., ... Reynolds, A. B. (2017). p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia. Journal of Clinical Investigation, 127(12), 4462-4476. https://doi.org/10.1172/JCI77217

p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia. / Short, Sarah P.; Kondo, Jumpei; Smalley-Freed, Whitney G.; Takeda, Haruna; Dohn, Michael R.; Powell, Anne E.; Carnahan, Robert H.; Washington, Mary K.; Tripathi, Manish; Payne, D. Michael; Jenkins, Nancy A.; Copeland, Neal G.; Coffey, Robert J.; Reynolds, Albert B.

In: Journal of Clinical Investigation, Vol. 127, No. 12, 01.12.2017, p. 4462-4476.

Research output: Contribution to journalArticle

Short, SP, Kondo, J, Smalley-Freed, WG, Takeda, H, Dohn, MR, Powell, AE, Carnahan, RH, Washington, MK, Tripathi, M, Payne, DM, Jenkins, NA, Copeland, NG, Coffey, RJ & Reynolds, AB 2017, 'p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia', Journal of Clinical Investigation, vol. 127, no. 12, pp. 4462-4476. https://doi.org/10.1172/JCI77217
Short SP, Kondo J, Smalley-Freed WG, Takeda H, Dohn MR, Powell AE et al. p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia. Journal of Clinical Investigation. 2017 Dec 1;127(12):4462-4476. https://doi.org/10.1172/JCI77217
Short, Sarah P. ; Kondo, Jumpei ; Smalley-Freed, Whitney G. ; Takeda, Haruna ; Dohn, Michael R. ; Powell, Anne E. ; Carnahan, Robert H. ; Washington, Mary K. ; Tripathi, Manish ; Payne, D. Michael ; Jenkins, Nancy A. ; Copeland, Neal G. ; Coffey, Robert J. ; Reynolds, Albert B. / p120-Catenin is an obligate haploinsufficient tumor suppressor in intestinal neoplasia. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 12. pp. 4462-4476.
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abstract = "p120-Catenin (p120) functions as a tumor suppressor in intestinal cancer, but the mechanism is unclear. Here, using conditional p120 knockout in Apc-sensitized mouse models of intestinal cancer, we have identified p120 as an “obligatory” haploinsufficient tumor suppressor. Whereas monoallelic loss of p120 was associated with a significant increase in tumor multiplicity, loss of both alleles was never observed in tumors from these mice. Moreover, forced ablation of the second allele did not further enhance tumorigenesis, but instead induced synthetic lethality in combination with Apc loss of heterozygosity. In tumor-derived organoid cultures, elimination of both p120 alleles resulted in caspase-3–dependent apoptosis that was blocked by inhibition of Rho kinase (ROCK). With ROCK inhibition, however, p120-ablated organoids exhibited a branching phenotype and a substantial increase in cell proliferation. Access to data from Sleeping Beauty mutagenesis screens afforded an opportunity to directly assess the tumorigenic impact of p120 haploinsufficiency relative to other candidate drivers. Remarkably, p120 ranked third among the 919 drivers identified. Cofactors α-catenin and epithelial cadherin (E-cadherin) were also among the highest scoring candidates, indicating a mechanism at the level of the intact complex that may play an important role at very early stages of of intestinal tumorigenesis while simultaneously restricting outright loss via synthetic lethality.",
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