A ‘Goldmine’ for digging cancer-specific targets: the genes essential for embryo development but non-essential for adult life

Yu, Xiaofeng; Xu, Jianming

doi:10.1093/jmcb/mjaa024

“…Cancer initiation is also associated with the activation of molecular signaling pathways that normally function during embryogenesis. However, developmental effects caused by mutation or loss of cancer-associated genes are often very different than adult phenotypes, as exemplified by early embryonic lethality versus adult cancer susceptibility 11 – 22 .…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, mutation or loss of cancer-associated genes can induce developmental effects in embryos that differ significantly from effects in adult animals. This frequently manifests as paradoxical embryonic lethality versus adult cancer susceptibility; examples include well-known tumor suppressor genes (Pten 11 , 12 , Rb 13 – 15 ), mediators of the DNA damage response (Atr 16 , 17 , Rad51 18 , 19 , Chek1 20 ), and others 21 , 22 . The constraints imposed by early embryonic lethality in these models is a limitation for investigations into how and why embryonic and adult cell populations respond so differently to certain cancer-associated genetic mutations.…”

Section: Introductionmentioning

confidence: 99%

brca2-mutant zebrafish exhibit context- and tissue-dependent alterations in cell phenotypes and response to injury

Kouprianov¹,

Selmek

²

,

Ferguson

³

et al. 2022

Sci Rep

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Cancer cells frequently co-opt molecular programs that are normally activated in specific contexts, such as embryonic development and the response to injury. Determining the impact of cancer-associated mutations on cellular phenotypes within these discrete contexts can provide new insight into how such mutations lead to dysregulated cell behaviors and subsequent cancer onset. Here we assess the impact of heritable BRCA2 mutation on embryonic development and the injury response using a zebrafish model (Danio rerio). Unlike most mouse models for BRCA2 mutation, brca2-mutant zebrafish are fully viable and thus provide a unique tool for assessing both embryonic and adult phenotypes. We find that maternally provided brca2 is critical for normal oocyte development and embryonic survival in zebrafish, suggesting that embryonic lethality associated with BRCA2 mutation is likely to reflect defects in both meiotic and embryonic developmental programs. On the other hand, we find that adult brca2-mutant zebrafish exhibit aberrant proliferation of several cell types under basal conditions and in response to injury in tissues at high risk for cancer development. These divergent effects exemplify the often-paradoxical outcomes that occur in embryos (embryonic lethality) versus adult animals (cancer predisposition) with mutations in cancer susceptibility genes such as BRCA2. The altered cell behaviors identified in brca2-mutant embryonic and adult tissues, particularly in adult tissues at high risk for cancer, indicate that the effects of BRCA2 mutation on cellular phenotypes are both context- and tissue-dependent.

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“…Cancer initiation is also associated with the activation of molecular signaling pathways that normally function during embryogenesis. However, developmental effects caused by mutation or loss of cancer-associated genes are often very different than adult phenotypes, as exemplified by early embryonic lethality versus adult cancer susceptibility [11][12][13][14][15][16][17][18][19][20][21][22] .…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, mutation or loss of cancer-associated genes can induce developmental effects in embryos that differ significantly from effects in adult animals. This frequently manifests as paradoxical embryonic lethality versus adult cancer susceptibility; examples include well-known tumor suppressor genes (Pten 11,12 , Rb 13–15 ), mediators of the DNA damage response (Atr 16,17 , Rad51 18,19 , Chek1 20 ), and others 21,22 . The constraints imposed by early embryonic lethality in these models is a limitation for investigations into how and why embryonic and adult cell populations respond so differently to certain cancer-associated genetic mutations.…”

Section: Introductionmentioning

confidence: 99%

brca2-mutant zebrafish exhibit context- and tissue-dependent alterations in cell phenotypes and response to injury

Kouprianov¹,

Selmek

²

,

Ferguson

³

et al. 2021

Preprint

0

View full text Add to dashboard Cite

Cancer cells frequently co-opt molecular programs that are normally activated in specific contexts, such as embryonic development and the response to injury. Determining the impact of cancer-associated mutations on cellular phenotypes within these discrete contexts can provide new insight into how such mutations lead to dysregulated cell behaviors and subsequent cancer onset. Here we assess the impact of heritable BRCA2 mutation on embryonic development and the injury response using a zebrafish model (Danio rerio). Unlike most mouse models for BRCA2 mutation, brca2-mutant zebrafish are fully viable and thus provide a unique tool for assessing both embryonic and adult phenotypes. We find that maternally provided brca2 is critical for normal oocyte development and embryonic survival in zebrafish, suggesting that embryonic lethality associated with BRCA2 mutation is likely to reflect defects in both meiotic and embryonic developmental programs. On the other hand, we find that adult brca2-mutant zebrafish exhibit aberrant proliferation of several cell types under basal conditions and in response to injury in tissues at high risk for cancer development. These divergent effects exemplify the often-paradoxical outcomes that occur in embryos (embryonic lethality) versus adult animals (cancer predisposition) with mutations in cancer susceptibility genes such as BRCA2. The altered cell behaviors identified in brca2-mutant embryonic and adult tissues, particularly in adult tissues at high risk for cancer, indicate that the effects of BRCA2 mutation on cellular phenotypes are both context- and tissue-dependent.

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“…Likewise, a better understating of how epigenetics influences the reactivation of fetal genes/the suppression of adult program may pave the way for new therapeutic solutions. As genes implicated in cell proliferation and differentiation play crucial roles during development, knockout of many of them is associated with embryonic/perinatal lethality [146]. Tissue specific or conditional gene targeting may represent a powerful tool to bypass the early lethality associated with global inactivation and thus to assess the contribution of genes during late development and PAH.…”

Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

Fetal Gene Reactivation in Pulmonary Arterial Hypertension: GOOD, BAD, or BOTH?

Lemay

¹

,

Awada

²

,

Shimauchi

³

et al. 2021

Cells

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Pulmonary arterial hypertension is a debilitating chronic disorder marked by the progressive obliteration of the pre-capillary arterioles. This imposes a pressure overload on the right ventricle (RV) pushing the latter to undergo structural and mechanical adaptations that inexorably culminate in RV failure and death. Thanks to the advances in molecular biology, it has been proposed that some aspects of the RV and pulmonary vascular remodeling processes are orchestrated by a subversion of developmental regulatory mechanisms with an upregulation of a suite of genes responsible for the embryo’s early growth and normally repressed in adults. In this review, we present relevant background regarding the close relationship between overactivation of fetal genes and cardiopulmonary remodeling, exploring whether the reawakening of developmental factors plays a causative role or constitutes a protective mechanism in the setting of PAH.

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A ‘Goldmine’ for digging cancer-specific targets: the genes essential for embryo development but non-essential for adult life

Cited by 11 publications

References 31 publications

brca2-mutant zebrafish exhibit context- and tissue-dependent alterations in cell phenotypes and response to injury

brca2-mutant zebrafish exhibit context- and tissue-dependent alterations in cell phenotypes and response to injury

brca2-mutant zebrafish exhibit context- and tissue-dependent alterations in cell phenotypes and response to injury

Fetal Gene Reactivation in Pulmonary Arterial Hypertension: GOOD, BAD, or BOTH?

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