DCC constrains tumour progression via its dependence receptor activity

Castets, Marie; Broutier, Laura; Molin, Yann; Brevet, Marie; Chazot, G; Gadot, Nicolas; Paquet, Armelle; Mazelin, Laetitia; Jarrosson-Wuillème, Loraine; Scoazec, Jean‐Yves; Bernet, Agnès; Mehlen, Patrick

doi:10.1038/nature10708

Cited by 98 publications

(111 citation statements)

References 18 publications

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“…37 Dcc mutations are found in~2.5% of COSMIC samples compared with~0.5% for krm1. However, since dcc is a gene three times longer than krm1, and therefore more likely to accumulate mutations, the frequency of krm1 mutations in cancers appears comparable to that of dcc.…”

Section: Discussionmentioning

confidence: 95%

Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner

2015

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In multicellular organisms, a tight control of cell death is required to ensure normal development and tissue homeostasis. Improper function of apoptotic or survival pathways can not only affect developmental programs but also favor cancer progression. Here we describe a novel apoptotic signaling pathway involving the transmembrane receptor Kremen1 and its ligand, the Wnt-antagonist Dickkopf1. Using a whole embryo culture system, we first show that Dickkopf1 treatment promotes cell survival in a mouse model exhibiting increased apoptosis in the developing neural plate. Remarkably, this effect was not recapitulated by chemical Wnt inhibition. We then show that Dickkopf1 receptor Kremen1 is a bona fide dependence receptor, triggering cell death unless bound to its ligand. We performed Wnt-activity assays to demonstrate that the pro-apoptotic and anti-Wnt functions mediated by Kremen1 are strictly independent. Furthermore, we combined phylogenetic and mutagenesis approaches to identify a specific motif in the cytoplasmic tail of Kremen1, which is (i) specifically conserved in the lineage of placental mammals and (ii) strictly required for apoptosis induction. Finally, we show that somatic mutations of kremen1 found in human cancers can affect its pro-apoptotic activity, supporting a tumor suppressor function. Our findings thus reveal a new Wnt-independent function for Kremen1 and Dickkopf1 in the regulation of cell survival with potential implications in cancer therapies.

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Section: Discussionmentioning

confidence: 95%

Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner

2015

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“…Both DCC and UNC5C have been suggested to be colon cancer tumor suppressors because their expression is lost or markedly decreased in the vast majority of colorectal cancers (17)(18)(19)(20). Moreover, inactivation of UNC5C or specific inactivation of DCC's proapoptotic activity in mice was shown to promote intestinal tumor progression (20,21). Moreover, it was recently shown that missense mutations in UNC5C are associated with risk of familial colorectal cancer (22).…”

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confidence: 99%

Dependence receptor TrkC is a putative colon cancer tumor suppressor

Genevois

Ichim

Coissieux

et al. 2013

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

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The TrkC neurotrophin receptor belongs to the functional dependence receptor family, members of which share the ability to induce apoptosis in the absence of their ligands. Such a trait has been hypothesized to confer tumor-suppressor activity. Indeed, cells that express these receptors are thought to be dependent on ligand availability for their survival, a mechanism that inhibits uncontrolled tumor cell proliferation and migration. TrkC is a classic tyrosine kinase receptor and therefore generally considered to be a protooncogene. We show here that TrkC expression is down-regulated in a large fraction of human colorectal cancers, mainly through promoter methylation. Moreover, we show that TrkC silencing by promoter methylation is a selective advantage for colorectal cell lines to limit tumor cell death. Furthermore, reestablished TrkC expression in colorectal cancer cell lines is associated with tumor cell death and inhibition of in vitro characteristics of cell transformation, as well as in vivo tumor growth. Finally, we provide evidence that a mutation of TrkC detected in a sporadic cancer is a loss-ofproapoptotic function mutation. Together, these data support the conclusion that TrkC is a colorectal cancer tumor suppressor.neurotrophin-3 | caspase-3 | genetic | epigenetic T he Trk tyrosine kinase receptors and their ligands, the neurotrophins, have been studied extensively for their role in nervous system development. However, TrkA was originally cloned as an oncogene from colon carcinoma tumors in which the TrkA kinase domain was fused to the tropomyosin gene in the extracellular domain (1). This discovery motivated a great number of studies, which showed that neurotrophins (NGF, BDNF, and NT-4/5, NT-3) and their respective Trk receptors (TrkA, TrkB, and TrkC), are all involved in various malignancies (for review, see ref.2). The initial (and still generally accepted) view is that Trks, like other tyrosine kinase receptors, are oncogenic receptors, and therefore pan-Trk kinase inhibitors are currently being tested in clinical trials (3-5). Somewhat surprisingly, however, it has turned out that, at least in tumors such as neuroblastoma and medulloblastoma, TrkA, TrkB, and TrkC behave very differently, despite their close homology. TrkA and TrkC expression is associated with a good prognosis, whereas TrkB is expressed in very aggressive tumors (for review; see ref.2). The fact that the high expression of a tyrosine kinase receptor known to activate prooncogenic pathways (like the MAPK and PI3K-AKT pathways) is associated with a better outcome is counter intuitive, and suggests the possibility that TrkA and TrkC, rather than functioning solely as oncogenes, may also, in at least some cases, act as tumor suppressors. Although this notion may be ostensibly paradoxical, two recent independent studies have lent support to it, by demonstrating that both TrkA and TrkC, but not TrkB, act as dependence receptors (6, 7).Dependence receptors, which also include DCC (Deleted in Colorectal Carcinoma), UNC5H, Patched, Ne...

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“…DCC je tumor supresorový gen, ačkoliv o jeho jasném zařazení se vedou stále velké diskuze. Někdy je označován jako poslední obránce (Late Gate keeper), který limituje progresi tumoru navozením apoptózy [46]. Jeho funkcí je blokovat růst buňky v případě absence svého ligandu (netrin-1).…”

Section: DCCunclassified

Molecular Pathogenesis of Colorectal Cancer

Král¹,

Slyšková²,

Vodička³

et al. 2016

Klin Onkol

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2 Oddělení molekulární biologie nádorů, Ústav experimentální medicíny, AV ČR, v.v.i., Praha SouhrnVýchodiska: Kolorektální karcinom (colorectal cancer -CRC) je nádorové onemocnění tlustého střeva s každoročně dia gnostikovanými téměř 1,3 miliony nových pa cientů celosvětově. Mortalita na toto závažné nádorové onemocnění dosahuje již 8,5 %. Jedná se o 2. nečastější nádo-rové onemocnění u žen (1. nádor prsu) a 3. u mužů (1. nádor plic, 2. nádor prostaty). Tímto CRC patří vedle nádorů prsu, prostaty a plic k nejčastějším nádorovým onemocnění u mužů a žen na světě. V České republice je stále více než 50 % pa cientů s CRC dia gnostikováno v pokroči-lém stadiu (stadium III a IV). Z molekulárně genetického pohledu je CRC velice heterogenní onemocnění, na kterém se podílí mnoho faktorů. CRC má formu jak hereditární, kde dominují mutace v genech APC (FAP, aFAP), MMR (HNPCC) atd., jejíž výskyt se pohybuje okolo 5-10 %, tak formu sporadickou s výskytem 90-95 %, kde dochází k postupné akumulaci mutací v široké škále genů. Znalost genetické podstaty (APC, KRAS, MMR, mikroRNA, CIMP atd.) jak hereditární, tak sporadické formy CRC je nezbytná nejen pro zahájení léčby, ale také pro odhadnutí celkového rizika, prognózy a následného follow-up pa cienta. Závěr: Tento článek shrnuje dosavadní molekulárně genetické aspekty patogeneze CRC. Klíčová slovakolorektální karcinom -patogeneze -hereditární -sporadický -rizikové faktory SummaryBackground: Colorectal cancer (CRC) remains a major health burden with an incidence of 1.3 million new cases worldwide and a mortality of almost 8.5%. It is the 2 nd most common cancer in women (1 st breast carcinoma) and 3 rd most common in men (1 st lung carcinoma, 2 nd prostate carcinoma). CRC alongside breast, lung, prostate and stomach cancer is in the top five most common cancers in men and women worldwide. There are still more than 50% of CRC patients diagnosed with advanced disease (stage III and IV) in the Czech Republic. Genetically, CRC is a very heterogeneous disease with many factors playing key roles in pathogenesis. There are two types of CRC, hereditary with an incidence of between 5% and 10% with APC (FAP, aFAP) or MMR (HNPCC) genes affected, and sporadic colorectal cancer with an incidence of 90-95% with a lot of mutations in variable genes that accumulate during pathogenesis (APC, KRAS, MMR, microRNA, CIMP etc.). Knowledge of the molecular pathogenesis of CRC (hereditary, sporadic) is crucial for treatment, assessment of risk, prognosis, and patient follow-up. Conclusion: This article summarizes the molecular pathogenesis of sporadic and hereditary CRC.

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DCC constrains tumour progression via its dependence receptor activity

Cited by 98 publications

References 18 publications

Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner

Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner

Dependence receptor TrkC is a putative colon cancer tumor suppressor

Molecular Pathogenesis of Colorectal Cancer

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