CRIPTO/GRP78 Signaling Maintains Fetal and Adult Mammary Stem Cells Ex Vivo

Spike, Benjamin T.; Kelber, Jonathan A.; Booker, Evan; Kalathur, Madhuri; Rodewald, Rose; Lipianskaya, Julia; La, Justin; He, Marielle; Wright, Tracy; Klemke, Richard L.; Wahl, Geoffrey M.; Gray, Peter C.

doi:10.1016/j.stemcr.2014.02.010

Cited by 61 publications

(90 citation statements)

References 43 publications

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“…Targeting csGRP78 with a monoclonal antibody led to suppression of AKT signaling and tumor growth (45,46). CsGRP78 is also an obligatory binding partner for Cripto, a GPI-anchored cell-surface protein and an upstream regulator of the TGFβ pathway and of AKT (47,48). GRP78 has been shown to costain with p-AKT in PDAC (26); thus, similar mechanisms may apply.…”

Section: Discussionmentioning

confidence: 99%

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

Shen

Zhu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease in critical need of new therapeutic strategies. Here, we report that the stress-inducible 78-kDa glucose-regulated protein (GRP78/HSPA5), a key regulator of endoplasmic reticulum homeostasis and PI3K/AKT signaling, is overexpressed in the acini and PDAC of Pdx1-Cre;Kras G12D/+ ;p53 f/+ (PKC) mice as early as 2 mo, suggesting that GRP78 could exert a protective effect on acinar cells under stress, as during PDAC development. The PKC pancreata bearing wild-type Grp78 showed detectable PDAC by 3 mo and rapid subsequent tumor growth. In contrast, the PKC pancreata bearing a Grp78 f/+ allele (PKC78 f/+ mice) expressing about 50% of GRP78 maintained normal sizes during the early months, with reduced proliferation and suppression of AKT, S6, ERK, and STAT3 activation. Acinar-to-ductal metaplasia (ADM) has been identified as a key tumor initiation mechanism of PDAC. Compared with PKC, the PKC78 f/+ pancreata showed substantial reduction of ADM as well as pancreatic intraepithelial neoplasia-1 (PanIN-1), PanIN-2, and PanIN-3 and delayed onset of PDAC. ADM in response to transforming growth factor α was also suppressed in ex vivo cultures of acinar cell clusters isolated from mouse pancreas bearing targeted heterozygous knockout of Grp78 (c78 f/+ ) and subjected to 3D culture in collagen. We further discovered that GRP78 haploinsufficiency in both the PKC78 f/+ and c78 f/+ pancreata leads to reduction of epidermal growth factor receptor, which is critical for ADM initiation. Collectively, our studies establish a role for GRP78 in ADM and PDAC development.glucose-regulated protein 78 | GRP78 | pancreatic ductal adenocarcinoma | acinar-to-ductal metaplasia | Kras P ancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest diseases with limited therapeutic options and an overall 5-y survival rate of <10%; therefore, identification of targetable key players in tumor initiation as well as tumor maintenance is urgently needed (1). PDAC is believed to arise from a range of preneoplastic mucinous lesions with ductal morphology, pancreatic intraepithelial neoplasia (PanIN) being the most common in humans (2). About 90% of PDAC contains activating mutations of KRAS whereas 50-75% contain mutations in Tp53 (1). Mutationally activated oncogenic KRAS signals through the PI3K-PDK1-AKT pathway and the canonical mitogen-activated protein kinase pathway via RAF-MEK1/2-ERK1/2, as well as via positive feedback activation of receptor tyrosine kinases engaged by autocrine and paracrine stimuli (3). Although the histological appearance of PDAC suggests a ductal cell of origin, accumulating evidence reveals that PDAC originates primarily through transdifferentiation of acinar cells into ductal cells in a process referred to as acinar-to-ductal metaplasia (ADM), although centroacinar cells and pancreas precursor cells could also give rise to PDAC (2, 4, 5). To study PDAC, a pancreatic cancer mouse model mimicking human PDAC has been established using the pancreatic...

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Section: Discussionmentioning

confidence: 99%

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

Shen

Zhu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Its anti-apoptotic role has also been reported [79]. In addition it may regulate the TGF-β pathway, through the molecolar interaction with its ligand Crypto, an oncofetal GPI-anchored/secreted signaling protein, which plays a key role as a stem cell regulator [80]. For these reasons, Cripto/GRP78 complex represents a possible therapeutic strategy for the treatment of human cancer [81].…”

Section: Kda Glucose-regulated Protein Grp(hspa5) This Protein Alsmentioning

confidence: 99%

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

Pucci‐Minafra¹,

Cara²,

Musso³

et al. 2017

Preprint

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Abstract:The present investigation has been conducted on one hundred tissue fragments of breast cancer, collected and immediately cryopreserved following the surgical resection. The fragments were selected from patients with invasive ductal carcinoma of the breast, the most common and potentially aggressive type of mammary cancer, with the objective to increase the knowledge of breast cancer molecular markers, useful for diagnostic and prognostic categorization of patients, in assessing postsurgical therapeutic regimes. The proteomic screening, by 2D-IPG and mass spectrometry, allowed us to identify two main classes of protein clusters: proteins expressed ubiquitously at high levels in all patients, and proteins expressed sporadically among the same patients. Within the group of ubiquitous proteins, glycolytic enzymes and proteins with anti-apoptotic activity were predominant. Among the sporadic ones, proteins involved in cell motility, molecular chaperones and proteins involved in the detoxification appeared prevalent. The data of the present study indicates that the primary tumor growth is generally supported by two concurrent pathways: the inhibition of apoptosis and the stimulation of cellular proliferation. The second phase of the evolution of the tumor can be prematurely scheduled by the occasional presence of proteins involved in cell motility and in the defenses of the oxidative stress. To our knowledge this report on large-scales proteomics of breast cancer is currently a unique approach in the literature that offers the opportunity to evaluate the presence and recurrence of proteins to be used as prognostic indicators and susceptibility to metastasis in patients operated on for invasive ductal carcinoma of the breast.

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“…Cr-1 was also identified as a key factor in the hematopoietic stem cell niche. Together with the cofactor GRP78, Cr-1 has an essential role in the maintenance of dormant ES cells under hypoxia by regulating the HIF-1 complex [37] and in the maintenance of mammary stem cells ex vivo [38]. …”

Section: Role Of Cripto-1 In Embryogenesis and Stem Cell Maintenancementioning

confidence: 99%

“…Cripto-1 binding to GRP78 may be generally required for Cripto-1 function since treatment with a GRP78-directed antibody (N-20) that competitively blocks Cripto-1/GRP78 binding, or GRP78 knockdown, blocks Cripto-1 effects on Activin A, Activin B, TGF-β1 and Nodal signaling and also inhibits soluble Cripto-1-dependent activation of c-src, Erk/MAPK and PI3K/Akt pathways [61]. More recent studies indicate that soluble Cripto-1 signals via cell surface GRP78 to promote maintenance of hematopoietic stem cells [37] and both fetal and adult mammary stem cells [38]. In both of these studies, soluble Cripto-1 was shown to selectively regulate cells expressing high levels of surface GRP78, to activate the PI3K/Akt pathway and to promote stem cell maintenance ex vivo .…”

Section: Cripto-1 Interacting Partners In Cellular Signalingmentioning

confidence: 99%

The multifaceted role of the embryonic gene Cripto-1 in cancer, stem cells and epithelial-mesenchymal transition

Klauzinska

Castro

Rangel

et al. 2014

Seminars in Cancer Biology

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Cripto-1 (CR-1)/Teratocarcinoma-derived growth factor1 (TDGF-1) is a cell surface glycosylphosphatidylinositol (GPI)-linked glycoprotein that can function either in cis (autocrine) or in trans (paracrine). The cell membrane cis form is found in lipid rafts and endosomes while the trans acting form lacking the GPI anchor is soluble. As a member of the epidermal growth factor (EGF)/Cripto-1-FRL-1-Cryptic (CFC) family, CR-1 functions as an obligatory co-receptor for the transforming growth factor-β (TGF-β) family members, Nodal and growth and differentiation factors 1 and 3 (GDF1/3) by activating Alk4/Alk7 signaling pathways that involve Smads 2, 3 and 4. In addition, CR-1 can activate non-Smad-dependent signaling elements such as PI3K, Akt and MAPK. Both of these pathways depend upon the 78 kDa glucose regulated protein (GRP78). Finally, CR-1 can facilitate signaling through the canonical Wnt/β-catenin and Notch/Cbf-1 pathways by functioning as a chaperone protein for LRP5/6 and Notch, respectively. CR-1 is essential for early embryonic development and maintains embryonic stem cell pluripotentiality. CR-1 performs an essential role in the etiology and progression of several types of human tumors where it is expressed in a population of cancer stem cells (CSCs) and facilitates epithelial-mesenchymal transition (EMT). In this context, CR-1 can significantly enhance tumor cell migration, invasion and angiogenesis. Collectively, these facts suggest that CR-1 may be an attractive target in the diagnosis, prognosis and therapy of several types of human cancer.

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CRIPTO/GRP78 Signaling Maintains Fetal and Adult Mammary Stem Cells Ex Vivo

Cited by 61 publications

References 43 publications

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

The multifaceted role of the embryonic gene Cripto-1 in cancer, stem cells and epithelial-mesenchymal transition

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