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Atypical protein kinase C iota (PKC?/?) ensures mammalian development by establishing the maternal-fetal exchange interface.

ABSTRACT: In utero mammalian development relies on the establishment of the maternal-fetal exchange interface, which ensures transportation of nutrients and gases between the mother and the fetus. This exchange interface is established via development of multinucleated syncytiotrophoblast cells (SynTs) during placentation. In mice, SynTs develop via differentiation of the trophoblast stem cell-like progenitor cells (TSPCs) of the placenta primordium, and in humans, SynTs are developed via differentiation of villous cytotrophoblast (CTB) progenitors. Despite the critical need in pregnancy progression, conserved signaling mechanisms that ensure SynT development are poorly understood. Herein, we show that atypical protein kinase C iota (PKC?/?) plays an essential role in establishing the SynT differentiation program in trophoblast progenitors. Loss of PKC?/? in the mouse TSPCs abrogates SynT development, leading to embryonic death at approximately embryonic day 9.0 (E9.0). We also show that PKC?/?-mediated priming of trophoblast progenitors for SynT differentiation is a conserved event during human placentation. PKC?/? is selectively expressed in the first-trimester CTBs of a developing human placenta. Furthermore, loss of PKC?/? in CTB-derived human trophoblast stem cells (human TSCs) impairs their SynT differentiation potential both in vitro and after transplantation in immunocompromised mice. Our mechanistic analyses indicate that PKC?/? signaling maintains expression of GCM1, GATA2, and PPAR?, which are key transcription factors to instigate SynT differentiation programs in both mouse and human trophoblast progenitors. Our study uncovers a conserved molecular mechanism, in which PKC?/? signaling regulates establishment of the maternal-fetal exchange surface by promoting trophoblast progenitor-to-SynT transition during placentation.

SUBMITTER: Bhattacharya B

PROVIDER: S-EPMC7322033 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Atypical protein kinase C iota (PKCλ/ι) ensures mammalian development by establishing the maternal-fetal exchange interface.

Bhattacharya Bhaswati B Home Pratik P Ganguly Avishek A Ray Soma S Ghosh Ananya A Islam Md Rashedul MR French Valerie V Marsh Courtney C Gunewardena Sumedha S Okae Hiroaki H Arima Takahiro T Paul Soumen S

Proceedings of the National Academy of Sciences of the United States of America 20200608 25

In utero mammalian development relies on the establishment of the maternal-fetal exchange interface, which ensures transportation of nutrients and gases between the mother and the fetus. This exchange interface is established via development of multinucleated syncytiotrophoblast cells (SynTs) during placentation. In mice, SynTs develop via differentiation of the trophoblast stem cell-like progenitor cells (TSPCs) of the placenta primordium, and in humans, SynTs are developed via differentiation ...[more]

PMID: 32513715

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Project description:Triple-negative breast cancer (TNBC) is a distinct breast cancer subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu), and the patients with TNBC are often diagnosed with higher rates of recurrence and metastasis. Because of the absence of ER, PR and HER2/neu expressions, TNBC patients are insensitive to HER2-directed and endocrine therapies available for breast cancer treatment. Here, we report that expression of atypical protein kinase C isoform, PKCλ/ι, significantly increased and activated in all invasive breast cancer (invasive ductal carcinoma or IDC) subtypes including the TNBC subtype. Because of the lack of targeted therapies for TNBC, we choose to study PKCλ/ι signaling as a potential therapeutic target for TNBC. Our observations indicated that PKCλ/ι signaling is highly active during breast cancer invasive progression, and metastatic breast cancers, the advanced stages of breast cancer disease that developed more frequently in TNBC patients, are also characterized with high levels of PKCλ/ι expression and activation. Functional analysis in experimental mouse models revealed that depletion of PKCλ/ι significantly reduces TNBC growth as well as lung metastatic colonization. Furthermore, we have identified a PKCλ/ι-regulated gene signature consisting of 110 genes, which are significantly associated with indolent to invasive progression of human breast cancer and poor prognosis. Mechanistically, cytokines such as TGFβ and IL1β could activate PKCλ/ι signaling in TNBC cells and depletion of PKCλ/ι impairs NF-κB p65 (RelA) nuclear localization. We observed that cytokine-PKCλ/ι-RelA signaling axis, at least in part, involved in modulating gene expression to regulate invasion of TNBC cells. Overall, our results indicate that induction and activation of PKCλ/ι promote TNBC growth, invasion and metastasis. Thus, targeting PKCλ/ι signaling could be a therapeutic option for breast cancer, including the TNBC subtype.

Dataset Information

Atypical protein kinase C iota (PKC?/?) ensures mammalian development by establishing the maternal-fetal exchange interface.

Publications

Atypical protein kinase C iota (PKCλ/ι) ensures mammalian development by establishing the maternal-fetal exchange interface.

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