The Sprouty/Spred family as tumor suppressors: Coming of age

Kawazoe, Tetsuro; Taniguchi, Koji

doi:10.1111/cas.13999

Cited by 50 publications

(50 citation statements)

References 83 publications

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“…In contrast, but as expected from previous observations [44], Cdx2 expression increased along the anterior-posterior axis. Interestingly, Spred and Sprouty (Spry), which suppress the ERK pathway at its apex [45], were also more abundantly expressed in COL crypts. These observations indicate that the ERK axis is more stringently controlled in the COL, and that higher pathway activity is tolerated in the SI.…”

Section: Oncogene Naive Si and Col Crypts Significantly Differ In Erkmentioning

confidence: 99%

BRAFV600E drives dedifferentiation in small intestinal and colonic organoids and cooperates with mutant p53 and Apc loss in transformation

et al. 2020

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BRAFV600E confers poor prognosis and is associated with a distinct subtype of colorectal cancer (CRC). Little is known, however, about the genetic events driving the initiation and progression of BRAFV600E mutant CRCs. Recent genetic analyses of CRCs indicate that BRAFV600E often coexists with alterations in the WNT- and p53 pathways, but their cooperation remains ill-defined. Therefore, we systematically compared small and large intestinal organoids from mice harboring conditional BraffloxV600E, Trp53LSL-R172H, and/or Apcflox/flox alleles. Using these isogenic models, we observe tissue-specific differences toward sudden BRAFV600E expression, which can be attributed to different ERK-pathway ground states in small and large intestinal crypts. BRAFV600E alone causes transient proliferation and suppresses epithelial organization, followed by organoid disintegration. Moreover, BRAFV600E induces a fetal-like dedifferentiation transcriptional program in colonic organoids, which resembles human BRAFV600E-driven CRC. Co-expression of p53R172H delays organoid disintegration, confers anchorage-independent growth, and induces invasive properties. Interestingly, p53R172H cooperates with BRAFV600E to modulate the abundance of transcripts linked to carcinogenesis, in particular within colonic organoids. Remarkably, WNT-pathway activation by Apc deletion fully protects organoids against BRAFV600E-induced disintegration and confers growth/niche factor independence. Still, Apc-deficient BRAFV600E-mutant organoids remain sensitive toward the MEK inhibitor trametinib, albeit p53R172H confers partial resistance against this clinically relevant compound. In summary, our systematic comparison of the response of small and large intestinal organoids to oncogenic alterations suggests colonic organoids to be better suited to model the human situation. In addition, our work on BRAF-, p53-, and WNT-pathway mutations provides new insights into their cooperation and for the design of targeted therapies.

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Section: Oncogene Naive Si and Col Crypts Significantly Differ In Erkmentioning

confidence: 99%

BRAFV600E drives dedifferentiation in small intestinal and colonic organoids and cooperates with mutant p53 and Apc loss in transformation

et al. 2020

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“…However, as inappropriate activation of growth factor signalling can stimulate excessive cell growth and tumorigenesis, these signalling pathways must be tightly regulated. Sprouty proteins are negative regulators of RAS/ERK signalling via a number of mechanisms ( Kawazoe and Taniguchi, 2019 ; Mason et al, 2006 ; Masoumi-Moghaddam et al, 2014 ), and the importance of these proteins as tumour suppressors is highlighted by their reduced expression in a range of malignancies. For example, sprouty-2 expression is downregulated in renal cell carcinoma, hepatocellular carcinoma, epithelial ovarian cancer, non-small-cell lung carcinoma, chronic lymphocytic leukaemia, gastric cancer, breast cancer and prostate cancer ( Kawazoe and Taniguchi, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Identification of key features required for efficient S-acylation and plasma membrane targeting of sprouty-2

Locatelli

Lemonidis

Salaün

et al. 2020

Journal of Cell Science

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Sprouty-2 is an important regulator of growth factor signalling and a tumour suppressor protein. The defining feature of this protein is a cysteine-rich domain (CRD) that contains twenty-six cysteines and is modified by S-acylation. In this study, we show that the CRD of Sprouty-2 is differentially modified by S-acyltransferase enzymes. The high specificity/low activity zDHHC17 enzyme mediated restricted S-acylation of Sprouty-2, and cysteines-265/268 were identified as key targets of this enzyme. In contrast, the low specificity/high activity zDHHC3/zDHHC7 enzymes mediated more expansive modification of the Sprouty-2 CRD. Nevertheless, S-acylation by all enzymes enhanced Sprouty-2 expression, suggesting that S-acylation stabilises this protein. In addition, we identified two charged residues (aspartate-214 and lysine-223), present on opposite faces of a predicted alpha helix in the CRD, which are essential for S-acylation of Sprouty-2. Interestingly, mutations that perturbed S-acylation also led to a loss of plasma membrane localisation of Sprouty-2 in PC12 cells. This study provides insight into the mechanisms and outcomes of Sprouty-2 S-acylation, and highlights distinct patterns of S-acylation mediated by different classes of zDHHC enzymes.

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“…Different members of the Sprouty/Spred gene family, which are considered tumor suppressor genes, also participate in mammary branching morphogenesis by interfering with EGFR signaling activity [ 9 , 62 ]. Among these is Spry 1.…”

Section: Mammary Gland Structure and Developmentmentioning

confidence: 99%

Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination

Avagliano

Fiume

Ruocco

et al. 2020

Cancers

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The stromal microenvironment regulates mammary gland development and tumorigenesis. In normal mammary glands, the stromal microenvironment encompasses the ducts and contains fibroblasts, the main regulators of branching morphogenesis. Understanding the way fibroblast signaling pathways regulate mammary gland development may offer insights into the mechanisms of breast cancer (BC) biology. In fact, the unregulated mammary fibroblast signaling pathways, associated with alterations in extracellular matrix (ECM) remodeling and branching morphogenesis, drive breast cancer microenvironment (BCM) remodeling and cancer growth. The BCM comprises a very heterogeneous tissue containing non-cancer stromal cells, namely, breast cancer-associated fibroblasts (BCAFs), which represent most of the tumor mass. Moreover, the different components of the BCM highly interact with cancer cells, thereby generating a tightly intertwined network. In particular, BC cells activate recruited normal fibroblasts in BCAFs, which, in turn, promote BCM remodeling and metastasis. Thus, comparing the roles of normal fibroblasts and BCAFs in the physiological and metastatic processes, could provide a deeper understanding of the signaling pathways regulating BC dissemination. Here, we review the latest literature describing the structure of the mammary gland and the BCM and summarize the influence of epithelial-mesenchymal transition (EpMT) and autophagy in BC dissemination. Finally, we discuss the roles of fibroblasts and BCAFs in mammary gland development and BCM remodeling, respectively.

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The Sprouty/Spred family as tumor suppressors: Coming of age

Cited by 50 publications

References 83 publications

BRAFV600E drives dedifferentiation in small intestinal and colonic organoids and cooperates with mutant p53 and Apc loss in transformation

BRAFV600E drives dedifferentiation in small intestinal and colonic organoids and cooperates with mutant p53 and Apc loss in transformation

Identification of key features required for efficient S-acylation and plasma membrane targeting of sprouty-2

Influence of Fibroblasts on Mammary Gland Development, Breast Cancer Microenvironment Remodeling, and Cancer Cell Dissemination

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