2,792
Views
3
CrossRef citations to date
0
Altmetric
Oncology

R-spondin family biology and emerging linkages to cancer

, , , , & ORCID Icon
Pages 428-446 | Received 21 Aug 2022, Accepted 06 Jan 2023, Published online: 16 Jan 2023

References

  • Kim KA, Zhao J, Andarmani S, et al. R-Spondin proteins: a novel link to beta-catenin activation. Cell Cycle. 2006;5(1):23–26.
  • de Lau WB, Snel B, Clevers HC. The R-spondin protein family. Genome Biol. 2012;13(3):242.
  • de Lau W, Barker N, Low T, et al. Lgr5 homologues associate with WNT receptors and mediate R-spondin signalling. Nature. 2011;476(7360):293–297.
  • Glinka A, Dolde C, Kirsch N, et al. LGR4 and LGR5 are R-spondin receptors mediating wnt/β-catenin and wnt/PCP signalling. EMBO Rep. 2011;12(10):1055–1061.
  • Ohkawara B, Glinka A, Niehrs C. Rspo3 binds syndecan 4 and induces wnt/PCP signaling via clathrin-mediated endocytosis to promote morphogenesis. Dev Cell. 2011;20(3):303–314.
  • Zheng C, Zhou F, Shi LL, et al. R-spondin2 suppresses the progression of hepatocellular carcinoma via MAPK signaling pathway. Mol Cancer Res. 2020;18(10):1491–1499.
  • Sun R, He L, Lee H, et al. RSPO2 inhibits BMP signaling to promote self-renewal in acute myeloid leukemia. Cell Rep. 2021;36(7):109559.
  • Han X, Jin Y, Tan L, et al. Regulation of the follistatin gene by RSPO-LGR4 signaling via activation of the WNT/β-catenin pathway in skeletal myogenesis. Mol Cell Biol. 2014;34(4):752–764.
  • Tang Y, Xu Q, Hu L, et al. Tumor microenvironment-derived R-spondins enhance anti-tumor immunity to suppress tumor growth and sensitize for immune checkpoint blockade therapy. Cancer Discov. 2021;11(12):3142–3157.
  • Ter Steege EJ, Bakker ERM. The role of R-spondin proteins in cancer biology. Oncogene. 2021;40(47):6469–6478.
  • Gordon MD, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem. 2006;281(32):22429–22433.
  • Bejsovec A. Wnt pathway activation: new relations and locations. Cell. 2005;120(1):11–14.
  • Nam JS, Turcotte TJ, Smith PF, et al. Mouse cristin/R-spondin family proteins are novel ligands for the frizzled 8 and LRP6 receptors and activate beta-catenin-dependent gene expression. J Biol Chem. 2006;281(19):13247–13257.
  • Kim KA, Wagle M, Tran K, et al. R-Spondin family members regulate the wnt pathway by a common mechanism. Mol Biol Cell. 2008;19(6):2588–2596.
  • Li SJ, Yen TY, Endo Y, et al. Loss-of-function point mutations and two-furin domain derivatives provide insights about R-spondin2 structure and function. Cell Signal. 2009;21(6):916–925.
  • Ayadi L. Molecular modeling of the TSR domain of R-spondin 4. Bioinformation. 2008;3(3):119–123.
  • Han XH, Jin YR, Seto M, et al. A WNT/beta-catenin signaling activator, R-spondin, plays positive regulatory roles during skeletal myogenesis. J Biol Chem. 2011;286(12):10649–10659.
  • Hao HX, Xie Y, Zhang Y, et al. ZNRF3 promotes wnt receptor turnover in an R-spondin-sensitive manner. Nature. 2012;485(7397):195–200.
  • Kazanskaya O, Glinka A, del Barco Barrantes I, et al. R-Spondin2 is a secreted activator of wnt/beta-catenin signaling and is required for xenopus myogenesis. Dev Cell. 2004;7(4):525–534.
  • Lebensohn AM, Rohatgi R. R-spondins can potentiate WNT signaling without LGRs. Elife. 2018;7:e33126.
  • Lee S, Jun J, Kim WJ, et al. WNT signaling driven by R-spondin 1 and LGR6 in high-grade serous ovarian cancer. Anticancer Res. 2020;40(11):6017–6028.
  • Mertens F, Johansson B, Fioretos T, et al. The emerging complexity of gene fusions in cancer. Nat Rev Cancer. 2015;15(6):371–381.
  • Seeber A, Battaglin F, Zimmer K, et al. Comprehensive analysis of R-spondin fusions and RNF43 mutations implicate novel therapeutic options in colorectal cancer. Clin Cancer Res. 2022;28(9):1863–1870.
  • Seshagiri S, Stawiski EW, Durinck S, et al. Recurrent R-spondin fusions in colon cancer. Nature. 2012;488(7413):660–664.
  • Zhang Y, Ren J, Fang M, et al. Investigation of fusion gene expression in HCT116 cells. Oncol Lett. 2017;14(6):6962–6968.
  • Smith CA, Shoemaker CM, Roeszler KN, et al. Cloning and expression of R-Spondin1 in different vertebrates suggests a conserved role in ovarian development. BMC Dev Biol. 2008;8:72.
  • Zhang Y, Li F, Sun D, et al. Molecular analysis shows differential expression of R-spondin1 in zebrafish (Danio rerio) gonads. Mol Biol Rep. 2011;38(1):275–282.
  • Tomizuka K, Horikoshi K, Kitada R, et al. R-spondin1 plays an essential role in ovarian development through positively regulating wnt-4 signaling. Hum Mol Genet. 2008;17(9):1278–1291.
  • Choi Y, Qin Y, Berger MF, et al. Microarray analyses of newborn mouse ovaries lacking Nobox1. Biol Reprod. 2007;77(2):312–319.
  • De Cian MC, Gregoire EP, Le Rolle M, et al. R-spondin2 signaling is required for oocyte-driven intercellular communication and follicular growth. Cell Death Differ. 2020;27(10):2856–2871.
  • Nam JS, Park E, Turcotte TJ, et al. Mouse R-spondin2 is required for apical ectodermal ridge maintenance in the hindlimb. Dev Biol. 2007;311(1):124–135.
  • Kocer A, Pinheiro I, Pannetier M, et al. R-spondin1 and FOXL2 act into two distinct cellular types during goat ovarian differentiation. BMC Dev Biol. 2008;8:36.
  • Aoki M, Mieda M, Ikeda T, et al. R-spondin3 is required for mouse placental development. Dev Biol. 2007;301(1):218–226.
  • Kazanskaya O, Ohkawara B, Heroult M, et al. The wnt signaling regulator R-spondin 3 promotes angioblast and vascular development. Development. 2008;135(22):3655–3664.
  • Caruso M, Ferranti F, Corano Scheri K, et al. R-spondin 1/dickkopf-1/beta-catenin machinery is involved in testicular embryonic angiogenesis. PLOS One. 2015;10(4):e0124213.
  • Glass DA, 2nd, Bialek P, Ahn JD, et al. Canonical wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell. 2005;8(5):751–764.
  • Bell SM, Schreiner CM, Wert SE, et al. R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis. Development. 2008;135(6):1049–1058.
  • Hankenson KD, Sweetwyne MT, Shitaye H, et al. Thrombospondins and novel TSR-containing proteins, R-spondins, regulate bone formation and remodeling. Curr Osteoporos Rep. 2010;8(2):68–76.
  • Knight MN, Karuppaiah K, Lowe M, et al. R-spondin-2 is a wnt agonist that regulates osteoblast activity and bone mass. Bone Res. 2018;6:24.
  • Doherty L, Sanjay A. LGRs in skeletal tissues: an emerging role for Wnt-associated adult stem cell markers in bone. JBMR Plus. 2020;4(7):e10380.
  • Levin G, Zuber SM, Squillaro AI, et al. R-Spondin 1 (RSPO1) increases mouse intestinal organoid unit size and survival in vitro and improves tissue-engineered small intestine formation in vivo. Front Bioeng Biotechnol. 2020;8:476.
  • Jingsong Zhao K-AK, De Vera J, Palencia S, et al. R-Spondin1 protects mice from chemotherapy or radiation-induced oral mucositis through the canonical wnt/β-catenin pathway. Proc Natl Acad Sci USA. 2009;106(7):2331–2336.
  • Harnack C, Berger H, Antanaviciute A, et al. R-spondin 3 promotes stem cell recovery and epithelial regeneration in the Colon. Nat Commun. 2019;10(1):4368.
  • Sigal M, Reines MDM, Mullerke S, et al. R-spondin-3 induces secretory, antimicrobial Lgr5(+) cells in the stomach. Nat Cell Biol. 2019;21(7):812–823.
  • Yan KS, Janda CY, Chang J, et al. Non-equivalence of wnt and R-spondin ligands during Lgr5(+) intestinal stem-cell self-renewal. Nature. 2017;545(7653):238–242.
  • Greicius G, Kabiri Z, Sigmundsson K, et al. PDGFRalpha(+) pericryptal stromal cells are the critical source of wnts and RSPO3 for murine intestinal stem cells in vivo. Proc Natl Acad Sci USA. 2018;115(14):E3173–E3181.
  • Liu S, Yin Y, Yu R, et al. R-spondin3-LGR4 signaling protects hepatocytes against DMOG-induced hypoxia/reoxygenation injury through activating beta-catenin. Biochem Biophys Res Commun. 2018;499(1):59–65.
  • Wu L, Zhang W, Qian J, et al. R-spondin family members as novel biomarkers and prognostic factors in lung cancer. Oncol Lett. 2019;18(4):4008–4015.
  • Munguía-Reyes A, Balderas-Martínez YI, Becerril C, et al. R-Spondin-2 is upregulated in idiopathic pulmonary fibrosis and affects fibroblast behavior. Am J Respir Cell Mol Biol. 2018;59(1):65–76.
  • Coussy F, Lallemand F, Vacher S, et al. Clinical value of R-spondins in triple-negative and metaplastic breast cancers. Br J Cancer. 2017;116(12):1595–1603.
  • Le D, Durham J, Smith K, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Sci Justice. 2017;357(6349):409–413.
  • Doig K, Fellowes A, Scott P, et al. Tumour mutational burden: an overview for pathologists. Pathology. 2022;54(3):249–253.
  • Zhang Y, Wang X. Targeting the wnt/beta-catenin signaling pathway in cancer. J Hematol Oncol. 2020;13(1):165.
  • Krishnamurthy N, Kurzrock R. Targeting the wnt/beta-catenin pathway in cancer: update on effectors and inhibitors. Cancer Treat Rev. 2018;62:50–60.
  • Gurney A, Axelrod F, Bond CJ, et al. Wnt pathway inhibition via the targeting of frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci U S A. 2012;109(29):11717–11722.
  • Choi J, Lee K, Kang M, et al. In silico discovery of quinoxaline derivatives as novel LRP5/6-sclerostin interaction inhibitors. Bioorg Med Chem Lett. 2018;28(6):1116–1121.
  • Lee JH, Faderl S, Pagel JM, et al. Phase 1 study of CWP232291 in patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndrome. Blood Adv. 2020;4(9):2032–2043.
  • Thorne CA, Hanson AJ, Schneider J, et al. Small-molecule inhibition of wnt signaling through activation of casein kinase 1alpha. Nat Chem Biol. 2010;6(11):829–836.
  • Yu S, Wang Z, Su Z, et al. Gigantol inhibits wnt/beta-catenin signaling and exhibits anticancer activity in breast cancer cells. BMC Complement Altern Med. 2018;18(1):59.
  • Kavitha K, Vidya Priyadarsini R, Anitha P, et al. Nimbolide, a neem limonoid abrogates canonical NF-kappaB and wnt signaling to induce caspase-dependent apoptosis in human hepatocarcinoma (HepG2) cells. Eur J Pharmacol. 2012;681(1-3):6–14.
  • Nagano K. R-spondin signaling as a pivotal regulator of tissue development and homeostasis. Jpn Dent Sci Rev. 2019;55(1):80–87.
  • Hao HX, Jiang X, Cong F. Control of wnt receptor turnover by R-spondin-ZNRF3/RNF43 signaling module and its dysregulation in cancer. Cancers. 2016;8(6):54.
  • Tocci JM, Felcher CM, Garcia Sola ME, et al. R-spondin-mediated WNT signaling potentiation in mammary and breast cancer development. IUBMB Life. 2020;72(8):1546–1559.
  • Liu Q, Zhao Y, Xing H, et al. The role of R-spondin 1 through activating wnt/beta-catenin in the growth, survival and migration of ovarian cancer cells. Gene. 2019;689:124–130.
  • Lahde M, Heino S, Hogstrom J, et al. Expression of R-Spondin 1 in apc(min/+) mice suppresses growth of intestinal adenomas by altering wnt and transforming growth factor beta signaling. Gastroenterology. 2021;160(1):245–259.
  • Gong Y, Yuan S, Sun J, et al. R-Spondin 2 induces odontogenic differentiation of dental pulp stem/progenitor cells via regulation of wnt/beta-catenin signaling. Front Physiol. 2020;11:918.
  • Conboy CB, Velez-Reyes GL, Tschida BR, et al. R-spondin 2 drives liver tumor development in a yes-associated protein-dependent manner. Hepatol Commun. 2019;3(11):1496–1509.
  • Zhang L, Song Y, Ling Z, et al. R-spondin 2-LGR4 system regulates growth, migration and invasion, epithelial-mesenchymal transition and stem-like properties of tongue squamous cell carcinoma via wnt/beta-catenin signaling. EBioMedicine. 2019;44:275–288.
  • Al-Samadi A, Salo T. Understanding the role of the R-spondin 2-LGR4 system in tongue squamous cell carcinoma progression. EBioMedicine. 2019;44:8–9.
  • Chen Z, Zhang J, Yuan A, et al. R-spondin3 promotes the tumor growth of choriocarcinoma JEG-3 cells. Am J Physiol Cell Physiol. 2020;318(3):C664–C674.
  • Fischer MM, Yeung VP, Cattaruzza F, et al. RSPO3 antagonism inhibits growth and tumorigenicity in colorectal tumors harboring common wnt pathway mutations. Sci Rep. 2017;7(1):15270.
  • Fujiwara M, Kato S, Niwa Y, et al. C-mannosylation of R-spondin3 regulates its secretion and activity of wnt/beta-catenin signaling in cells. FEBS Lett. 2016;590(16):2639–2649.
  • Picco G, Petti C, Centonze A, et al. Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions. EMBO Mol Med. 2017;9(3):293–303.
  • Zhang M, Haughey M, Wang NY, et al. Targeting the wnt signaling pathway through R-spondin 3 identifies an anti-fibrosis treatment strategy for multiple organs. PLOS One. 2020;15(3):e0229445.
  • Rong X, Chen C, Zhou P, et al. R-spondin 3 regulates dorsoventral and anteroposterior patterning by antagonizing wnt/beta-catenin signaling in zebrafish embryos. PLOS One. 2014;9(6):e99514.
  • Scholz B, Korn C, Wojtarowicz J, et al. Endothelial RSPO3 controls vascular stability and pruning through non-canonical WNT/Ca(2+)/NFAT signaling. Dev Cell. 2016;36(1):79–93.
  • Zhang M, Zhang P, Liu Y, et al. RSPO3-LGR4 regulates osteogenic differentiation of human adipose-derived stem cells via ERK/FGF signalling. Sci Rep. 2017;7:42841.
  • Gu H, Tu H, Liu L, et al. RSPO3 is a marker candidate for predicting tumor aggressiveness in ovarian cancer. Ann Transl Med. 2020;8(21):1351.
  • Lai S, Cheng R, Gao D, et al. LGR5 constitutively activates NF-kappaB signaling to regulate the growth of intestinal crypts. Faseb J. 2020;34(11):15605–15620.