NODAL/TGFβ signalling mediates the self-sustained stemness induced by PIK3CAH1047R homozygosity in pluripotent stem cells

Madsen, Ralitsa R.; Longden, James; Knox, Rachel; Robin, Xavier; Völlmy, Franziska; MacLeod, Kenneth G.; Moniz, Larissa S.; Carragher, Neil O.; Linding, Rune; Vanhaesebroeck, Bart; Semple, Robert K.

doi:10.1101/753830

Cited by 5 publications

(20 citation statements)

References 88 publications

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“…At the level of the PI3K heterodimer itself, very few studies have attempted to determine the identity of the main PI3K catalytic isoform(s) responsible for pathway activation in PSCs. Treatment of hPSCs with a relatively low-dose (100 nM) of the PI3Kα-specific inhibitor BYL719 reduces AKT phosphorylation both at baseline and in response to different growth factors, whereas treatment with TGX221 at a dose (500 nM) that would inhibit both PI3Kβ and PI3Kδ has no effect [58,98,99]. These findings agree with the identification of PIK3CA as an essential gene in a recent knock-out CRISPR screen in haploid hPSCs [100].…”

Section: The Specific Pi3k Isoformsupporting

confidence: 85%

“…mESCs [64], however, PI3Kα and not PI3Kβ so far appears to be the main isoform responsible not only for promoting survival but also stemness in hPSCs [58,98,99].…”

Section: The Specific Pi3k Isoformmentioning

confidence: 99%

“…However, the supporting evidence is based on the use of the relatively non-specific inhibitors, LY294002 and PI-103, thus warranting additional confirmation. Arguing against this mechanism, GSK3 phosphorylation is ablated in response to PI3Kα-specific inhibition in wild-type as well as PIK3CA H1047R hPSCs, irrespective of the elevated ERK phosphorylation seen in PIK3CA mutant cells [99].…”

Section: Downstream Effectorsmentioning

confidence: 99%

“…Mainly performed in mouse ESCs treated with LY294002 or expressing dominant-negative PI3K regulators, some early studies linked PI3K activity to increased Nanog expression through a PI3Kβ-dependent but AKT-independent mechanism [64,132,133]. More recently, specific perturbation of PI3Kα by both genetic and pharmacological means revealed a previously unknown link between activation of this enzyme and acute dose-as well as time-dependent regulation of NODAL expression, prior to any changes in NANOG [58,99] a well-known transcriptional target of TGFβ/NODAL signalling [134]. Furthermore, homozygous PIK3CA H1047R hPSCs no longer require continuous PI3K pathway activation to sustain the enhanced stemness gene signature, consistent with their autocrine activation of TGFβ/NODAL signalling [99].…”

Section: A Note On Contextmentioning

confidence: 99%

“…More recently, specific perturbation of PI3Kα by both genetic and pharmacological means revealed a previously unknown link between activation of this enzyme and acute dose-as well as time-dependent regulation of NODAL expression, prior to any changes in NANOG [58,99] a well-known transcriptional target of TGFβ/NODAL signalling [134]. Furthermore, homozygous PIK3CA H1047R hPSCs no longer require continuous PI3K pathway activation to sustain the enhanced stemness gene signature, consistent with their autocrine activation of TGFβ/NODAL signalling [99]. Evidence from bona fide cancer models of oncogenic PI3K pathway activation also suggests that the stemness phenotype can become uncoupled from the original trigger and thus no longer reversible simply through PI3K inhibition [99,135,136].…”

Section: A Note On Contextmentioning

confidence: 99%

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PI3K in stemness regulation: from development to cancer

Madsen

2020

Biochemical Society Transactions

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The PI3K/AKT pathway is a key target in oncology where most efforts are focussed on phenotypes such as cell proliferation and survival. Comparatively, little attention has been paid to PI3K in stemness regulation, despite the emerging link between acquisition of stem cell-like features and therapeutic failure in cancer. The aim of this review is to summarise current known and unknowns of PI3K-dependent stemness regulation, by integrating knowledge from the fields of developmental, signalling and cancer biology. Particular attention is given to the role of the PI3K pathway in pluripotent stem cells (PSCs) and the emerging parallels to dedifferentiated cancer cells with stem cell-like features. Compelling evidence suggests that PI3K/AKT signalling forms part of a ‘core molecular stemness programme’ in both mouse and human PSCs. In cancer, the oncogenic PIK3CAH1047R variant causes constitutive activation of the PI3K pathway and has recently been linked to increased stemness in a dose-dependent manner, similar to observations in mouse PSCs with heterozygous versus homozygous Pten loss. There is also evidence that the stemness phenotype may become ‘locked’ and thus independent of the original PI3K activation, posing limitations for the success of PI3K monotherapy in cancer. Ongoing therapeutic developments for PI3K-associated cancers may therefore benefit from a better understanding of the pathway's two-layered and highly context-dependent regulation of cell growth versus stemness.

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Section: The Specific Pi3k Isoformsupporting

confidence: 85%

“…mESCs [64], however, PI3Kα and not PI3Kβ so far appears to be the main isoform responsible not only for promoting survival but also stemness in hPSCs [58,98,99].…”

Section: The Specific Pi3k Isoformmentioning

confidence: 99%

Section: Downstream Effectorsmentioning

confidence: 99%

Section: A Note On Contextmentioning

confidence: 99%

Section: A Note On Contextmentioning

confidence: 99%

See 3 more Smart Citations

PI3K in stemness regulation: from development to cancer

Madsen

2020

Biochemical Society Transactions

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When, where and which PIK3CA mutations are pathogenic in congenital disorders

Angulo‐Urarte

Graupera

2022

Nat Cardiovasc Res

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PIK3CA encodes for the class I PI3Kα isoform and is frequently mutated in cancer.Activating mutations in PIK3CA also cause a range of congenital disorders featuring asymmetric tissue overgrowth, known as the PIK3CA-related overgrowth spectrum (PROS), with the vasculature frequently involved. In PROS, PIK3CA mutations arise postzygotically during embryonic development leading to a mosaic distribution resulting in a variety of phenotypic features. A clear skewed pattern of overgrowth favouring some mesoderm and ectoderm-derived tissues is observed but is not understood. Here, we summarize current knowledge on the determinants of PIK3CA-related pathogenesis in PROS, including intrinsic factors such as cell lineage susceptibility and PIK3CA variant bias and extrinsic factors which refers to the environmental modifiers. Gaining biological understanding of PIK3CA mutations in PROS will contribute to unravel the onset and progression of these conditions, and ultimately impact on their treatment. Given that PIK3CA mutations are similar in PROS and cancer, deeper insight into one will also inform about the other.PIK3CA encodes for p110α, one of the four class I phosphatidylinositol 3-kinase (PI3K) catalytic subunits. p110α is an obligate heterodimer with a p85-type regulatory subunit, with no evidence of the existence of p85-free p110α [1][2][3][4] . For simplicity, we will use

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Transcriptomically-inferred PI3K activity and stemness show a counterintuitive correlation withPIK3CAgenotype in breast cancer

Madsen

Rueda

Robin

et al. 2020

Preprint

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ABSTRACTThe development of reliable, prognostically informative molecular tests to direct targeted cancer therapy is a major challenge. In 2019, the PI3Kα inhibitor alpelisib was approved for the treatment of advanced breast cancer, in combination with the oestrogen receptor degrader fulvestrant, with some evidence for improved therapeutic response in patients classified as having tumours which were positive for mutation in PIK3CA, the gene encoding PI3Kα. Using human pluripotent stem cells, we recently demonstrated that the PIK3CAH1047R oncogenic hotspot variant shows marked PIK3CA allele dose-dependent activation of PI3K signalling and induction of self-sustained stemness. Together with recent discoveries of multi-copy and double-cis PIK3CA mutations in human cancers, this calls for a re-evaluation of the PIK3CA genotype-phenotype relationship and the current use of binary stratification by PIK3CA mutation status. Using computational analyses, we thus investigated the relationship between PIK3CA mutational status, PI3K activity/signalling strength and stemness. Stemness and PI3K activity scores were calculated using open-source methods and well-established transcriptional signatures. We report that a high PI3K pathway activity score, but not the presence of PIK3CA mutation per se, predicts increased breast cancer dedifferentiation and higher stemness, correlating with reduced overall survival. Our data (1) corroborate reports that the presence of a PIK3CA mutation per se does not predict high PI3K pathway activation or poor prognosis; (2) suggest that stratification of breast cancer for PI3K-based therapy might benefit from the use of a PI3K pathway activity score rather than binary PIK3CA mutation status alone; (3) suggest that combination of PI3K pathway inhibitors with differentiation-promoting treatments warrants evaluation in aggressive breast cancers with high PI3K activity and stemness scores.

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NODAL/TGFβ signalling mediates the self-sustained stemness induced by PIK3CA^H1047R homozygosity in pluripotent stem cells

Cited by 5 publications

References 88 publications

PI3K in stemness regulation: from development to cancer

PI3K in stemness regulation: from development to cancer

When, where and which PIK3CA mutations are pathogenic in congenital disorders

Transcriptomically-inferred PI3K activity and stemness show a counterintuitive correlation withPIK3CAgenotype in breast cancer

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