Oncogenic activation of PI3K induces progenitor cell differentiation to suppress epidermal growth

Ying, Zhe; Sandoval, Madeline; Beronja, Slobodan

doi:10.1038/s41556-018-0218-9

Cited by 50 publications

(69 citation statements)

References 70 publications

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“…28 Previous studies have highlighted that PI3K signaling is crucial for embryonic development and plays an important role in the control of pluripotency and differentiation. 30,31 In this study, we confirm a novel PROS phenotype with isolated muscle overgrowth and ectopic muscles and show evidence that PIK3CA regulates cell fate in early human embryonic development. 30,31 In this study, we confirm a novel PROS phenotype with isolated muscle overgrowth and ectopic muscles and show evidence that PIK3CA regulates cell fate in early human embryonic development.…”

Section: Introductionsupporting

confidence: 72%

“…29 Recent studies have also highlighted a prominent role for PI3K signaling during cell differentiation and determination of cell fate in mouse models. 30,31 In this study, we confirm a novel PROS phenotype with isolated muscle overgrowth and ectopic muscles and show evidence that PIK3CA regulates cell fate in early human embryonic development.…”

Section: Introductionsupporting

confidence: 72%

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Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth

et al. 2019

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PIK3CA-related overgrowth spectrum is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic PIK3CA mutations. Here, we report clinical data and molecular findings from two patients with congenital muscular upper limb overgrowth and aberrant anatomy. During debulking surgery, numerous ectopic muscles were found in the upper limbs of the patients. DNA sequencing, followed by digital polymerase chain reaction, was performed on DNA extracted from biopsies from hypertrophic ectopic muscles and identified the somatic mosaic PIK3CA hotspot mutations c.3140A > G, p.(His1047Arg) and c.1624G > A, p.(Glu542Lys) in a male (patient 1) and a female (patient 2) patient, respectively. Patient 1 had four ectopic muscles and unilateral isolated muscular overgrowth while patient 2 had 13 ectopic muscles and bilateral isolated muscular overgrowth of both upper limbs, indicating that her mutation occurred at early pre-somitic mesoderm state. The finding of PIK3CA mutations in ectopic muscles highlights the importance of PIK3CA in cell fate in early human embryonic development. Moreover, our findings provide evidence that the disease phenotype depends on the timing of PIK3CA mutagenesis during embryogenesis and confirm the diagnostic entity PIK3CA-related muscular overgrowth with ectopic accessory muscles. K E Y W O R D Saccessory, cell fate, ectopic, muscle hypertrophy, muscular hypertrophy, PIK3CA, PROS Tobias Laurell and Ann Nordgren contributed equally.

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Section: Introductionsupporting

confidence: 72%

Section: Introductionsupporting

confidence: 72%

Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth

et al. 2019

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“…In this regard, we did not find evidence for cell cycle blockade in MEFs expressing an endogenous heterozygous PIK3CA H1047R allele [72]. Oncogenic activation of PI3K signaling has also been shown to elicit senescence in some cellular contexts [91,95,96] but not in others [72,97]. Other than being context-dependent, evidence has been presented that PIK3CA activation is a weaker inducer of senescence than oncogenic Ras [98].…”

Section: Cell Cycle Block By Constitutive Pi3k (Over)activation?contrasting

confidence: 60%

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

Vanhaesebroeck

Bilanges

Madsen

et al. 2019

Preprint

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Genetic activation of the class I PI3K pathway is very common in cancer. This mostly results from oncogenic mutations in PIK3CA, the gene encoding the ubiquitously expressed PI3Kα catalytic subunit, or from inactivation of the PTEN tumour suppressor, a lipid phosphatase which opposes class I PI3K signalling. The clinical impact of PI3K inhibitors in solid tumours, aimed at dampening cancercell-intrinsic PI3K activity, has thus far been limited. Challenges include poor drug tolerance, incomplete pathway inhibition and pre-existing or inhibitor-induced resistance. The principle of pharmacologically targeting cancer-cell-intrinsic PI3K activity also assumes that all cancer-promoting effects of PI3K activation are reversible, which might not be the case. Emerging evidence suggests that genetic PI3K pathway activation can induce and/or allow cells to tolerate chromosomal instability, which -even if occurring in a low fraction of the cell population -might help to facilitate and/or drive tumour evolution. While it is clear that such genomic events cannot be reverted pharmacologically, a role for PI3K in the regulation of chromosomal instability could be exploited by using PI3K pathway inhibitors to prevent those genomic events from happening and/or reduce the pace at which they are occurring, thereby dampening cancer development or progression. Such an impact might be most effective in tumours with clonal PI3K activation and achievable at lower drug doses than the maximum-tolerated doses of PI3K inhibitors currently used in the clinic.

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“…Remarkably, in aged sun-exposed skin, homeostasis and the architecture of the epidermis is maintained despite prevalent clones of cells containing oncogenic mutations [1]. Recent work has highlighted oncogene-induced differentiation and active elimination of mutant clones as two mechanisms of epidermal robustness, suggesting there are multiple modes of response to perturbation [2,3]. Homeostasis requires that gain of cells (proliferation) must be balanced with loss of cells (differentiation or cell death).…”

Section: Resultsmentioning

confidence: 99%

Regulated spindle orientation buffers tissue growth in the epidermis

Morrow

Underwood

Seldin

et al. 2019

Preprint

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SummaryTissue homeostasis requires a balance between progenitor cell proliferation and loss. Mechanisms that maintain this robust balance are needed to avoid tissue loss or overgrowth. Here we demonstrate that regulation of spindle orientation/asymmetric cell divisions is one mechanism that is used to buffer changes in proliferation and tissue turnover in mammalian skin. Genetic and pharmacologic experiments demonstrate that asymmetric cell divisions were increased in hyperproliferative conditions and decreased under hypoproliferative conditions. Further, active K-Ras also increased the frequency of asymmetric cell divisions. Disruption of spindle orientation in combination with constitutively active K-Ras resulted in massive tissue overgrowth. Together, these data highlight the essential roles of spindle orientation in buffering tissue homeostasis in response to perturbations.

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Oncogenic activation of PI3K induces progenitor cell differentiation to suppress epidermal growth

Cited by 50 publications

References 70 publications

Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth

Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

Regulated spindle orientation buffers tissue growth in the epidermis

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