Gpr125 is a unifying hallmark of multiple mammary progenitors coupled to tumor latency

Spina, Elena; Simundza, Julia; Incassati, Angela; Chandramouli, Anupama; Kugler, Matthias C.; Lin, Ziyan; Khodadadi‐Jamayran, Alireza; Watson, Christine J.; Cowin, Pamela

doi:10.1038/s41467-022-28937-x

Cited by 12 publications

(8 citation statements)

References 75 publications

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“…Adgra3 is expressed throughout the female urogenital system, with higher expression in pre-pubertal mice, which drops precipitously after sexual maturation. This is consistent with patterns of Adgra3 expression in the lacrimal and mammary glands, which also undergo significant postnatal development, where expression is associated with undifferentiated cell states and migratory processes associated with concurrent lumen formation [ 41 , 42 ].…”

Section: Discussionsupporting

confidence: 80%

“…1 c). Given the high ADGRA3 expression in spermatogonial stem cells [ 37 – 40 ], we investigated ADGRA3 within the ovaries utilizing transgenic mice expressing ADGRA3 fused to β-galactosidase at the first transmembrane domain [ 38 , 40 – 42 ]. In these mice, ADGRA3 was predominantly located in the corpus luteum (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…ADGRA3 was initially described as a marker for spermatogonial stem cells [ 37 – 39 ], and we recently identified it as a factor of male infertility due to ejaculatory duct obstruction in half of all male mice lacking ADGRA3 [ 40 ]. Moreover, Spina et al recently described ADGRA3 expression on progenitor cells at the leading tips of the lacrimal ducts, which was required for proper tear film in mice, and on migrating progenitor cells at the invasive tips of ducts and branches during mammary development in mice [ 41 , 42 ]. The direct cellular signaling mechanism for ADGRA3 has yet to be unraveled, but the receptor is expressed at the cell surface, where it constitutively internalizes [ 43 ].…”

Section: Introductionmentioning

confidence: 99%

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High incidence of imperforate vagina in ADGRA3-deficient mice

Kvam,

Nybo,

Torz

et al. 2024

BMC Biol

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Background Ten percent of the female population suffers from congenital abnormalities of the vagina, uterus, or oviducts, with severe consequences for reproductive and psychological health. Yet, the underlying causes of most of these malformations remain largely unknown. ADGRA3 (GPR125) is involved in WNT signaling and planar cell polarity, mechanisms vital to female reproductive tract development. Although ADGRA3 is a well-established spermatogonial stem cell marker, its role within the female urogenital system remains unclear. Results In this study, we found Adgra3 to be expressed throughout the murine female urogenital system, with higher expression pre-puberty than after sexual maturation. We generated a global Adgra3−/− mouse line and observed imperforate vagina in 44% of Adgra3−/− females, resulting in distension of the reproductive tract and infertility. Ovarian morphology, plasma estradiol, ovarian Cyp19a1, and vaginal estrogen receptor α (Esr1) expression were unaffected. However, compared to controls, a significantly lower bone mineral density was found in Adgra3−/− mice. Whereas vaginal opening in mice is an estrogen-dependent process, 17β-estradiol treatment failed to induce vaginal canalization in Adgra3−/− mice. Furthermore, a marked reduction in vaginal and ovarian progesterone receptor expression was observed concomitant with an upregulation of apoptotic regulators Bcl2, Bid, and Bmf in adult Adgra3−/− females with a closed vagina. Conclusions Our collective results shed new insights into the complex mechanisms by which the adhesion receptor ADGRA3 regulates distal vaginal tissue remodeling during vaginal canalization via altered sex hormone responsiveness and balance in apoptotic regulators. This highlights the potential of ADGRA3 as a target in diagnostic screening and/or therapy for obstructive vaginal malformations in humans.

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Section: Discussionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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High incidence of imperforate vagina in ADGRA3-deficient mice

Kvam,

Nybo,

Torz

et al. 2024

BMC Biol

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“…We pinpoint this population in mammary ducts in situ , and FABP7 enables the purification of a ductal luminal progenitor subset for the first time. The ductal distribution pattern of FABP7 in situ is similar to GPR125+ basal progenitors and luminal label retaining cells that were reported in mice 41,42 , supporting breast ducts as an untapped reservoir for adult progenitors in mouse and human.…”

Section: Discussionsupporting

confidence: 75%

FABP7 Progenitors are a Targetable Metabolic Root in theBRCA1Breast

McCloskey,

Zhang,

Waas

et al. 2023

Preprint

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It has been nearly 3 decades since the discovery of theBRCA1/2genes and their link to breast cancer risk, with prophylactic mastectomy remaining the primary management option for these high-risk mutation carriers. The current paucity of interception strategies is due to undefined, targetable cancer precursor populations in the high-risk breast. Despite known cellular alterations in theBRCA1breast, epithelial populations at the root of unwarranted cell state transitions remain unresolved. Here, we identify a root progenitor population that is dysregulated inBRCA1carriers stemming from the metabolic role of BRCA1. This fatty-acid binding protein 7 (FABP7) expressing luminal progenitor population is spatially confined to the mammary ducts, has enhanced clonogenic capacity, and is the predicted origin of mixed basal-luminal differentiation in theBRCA1but notBRCA2breast. We show global H3K27 acetylation is reduced within ductal FABP7 cells inBRCA1carriersin situ, linking to a non-canonical metabolic role of BRCA1 in regulating acetyl-CoA pools andde novofatty acid synthesis. We demonstrate FABP7 progenitor capacity is preferentially ablated inBRCA1carriers through inhibition of fatty acid metabolism using an FDA-approved fatty acid synthase (FASN) inhibitor. This study lays the foundation for metabolic control of breast progenitor dynamics to mitigate breast cancer risk in theBRCA1breast.

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“…It generates nuclear ATP to fuel chromatin remodeling, gene expression, and proliferation [98]. Also, GPR125 encodes a GPCR that regulates epithelial polarity [99] and is associated with poor outcome in breast cancer [100]. Finally, MET, which encodes the hepatocyte growth factor receptor (HGFR), is a proto-oncogenic receptor tyrosine kinase found to be coregulated with Notch in physiologic as well as several pathologic conditions, including in gastric and breast cancer cells [101][102][103][104][105].…”

Section: Discussionmentioning

confidence: 99%

Novel determinants of NOTCH1 trafficking and signaling in breast epithelial cells

Kobia

Almeida

Carminati

et al. 2023

Preprint

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The evolutionarily conserved Notch pathway controls cell–cell communication during development and in adult metazoans. It influences cell fate decisions, cell proliferation and cell differentiation, and contributes to the maintenance of normal tissue homeostasis. Consequently, misregulation of the Notch pathway is associated with a wide range of diseases, including congenital disorders and cancers with little to no cure. Signaling by Notch receptors is regulated by a complex set of cellular processes that include maturation and trafficking to the plasma membrane, endocytic uptake and sorting, lysosomal and proteasomal degradation, and ligand-dependent and independent proteolytic cleavages. We devised assays to follow quantitively the lifetime of endogenous human NOTCH1 receptor in breast epithelial cells in culture. Based on such analysis, we executed a high-content screen of 2749 human genes for which modulatory compounds exist, to identify new regulators of Notch signaling activation that might be amenable to pharmacologic intervention. We uncovered 39 new NOTCH1 genetic modulators that affect different steps of NOTCH1 cellular dynamics. In particular, we find thatPTPN23andHCN2act as positive NOTCH1 regulators by promoting endocytic trafficking and NOTCH1 maturation in the Golgi apparatus, respectively, whileSGK3serves as a negative regulator that can be modulated by pharmacologic inhibition. Our findings might be relevant in the search of new strategies to counteract pathologic Notch signaling.

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Gpr125 is a unifying hallmark of multiple mammary progenitors coupled to tumor latency

Cited by 12 publications

References 75 publications

High incidence of imperforate vagina in ADGRA3-deficient mice

High incidence of imperforate vagina in ADGRA3-deficient mice

FABP7 Progenitors are a Targetable Metabolic Root in theBRCA1Breast

Novel determinants of NOTCH1 trafficking and signaling in breast epithelial cells

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