LGN Loss Randomizes Spindle Orientation and Accelerates Tumorigenesis in PTEN-deficient Epidermis

Overview

Journal Mol Biol Cell

Specialties Cell Biology
Molecular Biology

Date 2023 Nov 22

PMID 37991903

Authors

Sophie Viala

Charlotte Hadjadj

Vandana Nathan

Marie-Christine Guiot

Luke McCaffrey

Katie Cockburn

Maxime Bouchard

Affiliations

Soon will be listed here.

Abstract

Loss of cell polarity and disruption of tissue organization are key features of tumorigenesis that are intrinsically linked to spindle orientation. Epithelial tumors are often characterized by spindle orientation defects, but how these defects impact tumor formation driven by common oncogenic mutations is not fully understood. Here, we examine the role of spindle orientation in adult epidermis by deleting a key spindle regulator, LGN, in normal tissue and in a PTEN-deficient mouse model. We report that LGN deficiency in PTEN mutant epidermis leads to a threefold increase in the likelihood of developing tumors on the snout, and an over 10-fold increase in tumor burden. In this tissue, loss of LGN alone increases perpendicular and oblique divisions of epidermal basal cells, at the expense of a planar orientation of division. PTEN loss alone does not significantly affect spindle orientation in these cells, but the combined loss of PTEN and LGN fully randomizes basal spindle orientation. A subset of LGN- and PTEN-deficient animals have increased amounts of proliferative spinous cells, which may be associated with tumorigenesis. These results indicate that loss of LGN impacts spindle orientation and accelerates epidermal tumorigenesis in a PTEN-deficient mouse model.

References

Bergstralh D, Lovegrove H, St Johnston D . Lateral adhesion drives reintegration of misplaced cells into epithelial monolayers. Nat Cell Biol. 2015; 17(11):1497-1503. PMC: 4878657. DOI: 10.1038/ncb3248. View

Kaushik R, Yu F, Chia W, Yang X, Bahri S . Subcellular localization of LGN during mitosis: evidence for its cortical localization in mitotic cell culture systems and its requirement for normal cell cycle progression. Mol Biol Cell. 2003; 14(8):3144-55. PMC: 181556. DOI: 10.1091/mbc.e03-04-0212. View

Liu Y, Du X, Zhang S, Liu Y, Zhang Q, Yin Q . PTEN regulates spindle assembly checkpoint timing through MAD1 in interphase. Oncotarget. 2017; 8(58):98040-98050. PMC: 5716712. DOI: 10.18632/oncotarget.20532. View

Lechler T, Fuchs E . Asymmetric cell divisions promote stratification and differentiation of mammalian skin. Nature. 2005; 437(7056):275-80. PMC: 1399371. DOI: 10.1038/nature03922. View

Matsui T, Amagai M . Dissecting the formation, structure and barrier function of the stratum corneum. Int Immunol. 2015; 27(6):269-80. DOI: 10.1093/intimm/dxv013. View

Williams S, Ratliff L, Postiglione M, Knoblich J, Fuchs E . Par3-mInsc and Gαi3 cooperate to promote oriented epidermal cell divisions through LGN. Nat Cell Biol. 2014; 16(8):758-69. PMC: 4159251. DOI: 10.1038/ncb3001. View

Pfannenstein A, Macara I . A junction-dependent mechanism drives murine mammary cell intercalation for ductal elongation. Dev Cell. 2023; 58(13):1126-1138.e4. PMC: 10524519. DOI: 10.1016/j.devcel.2023.04.009. View

Lechler T, Mapelli M . Spindle positioning and its impact on vertebrate tissue architecture and cell fate. Nat Rev Mol Cell Biol. 2021; 22(10):691-708. PMC: 10544824. DOI: 10.1038/s41580-021-00384-4. View

Gonzales K, Fuchs E . Skin and Its Regenerative Powers: An Alliance between Stem Cells and Their Niche. Dev Cell. 2017; 43(4):387-401. PMC: 5797699. DOI: 10.1016/j.devcel.2017.10.001. View

10.

Suzuki A, Itami S, Ohishi M, Hamada K, Inoue T, Komazawa N . Keratinocyte-specific Pten deficiency results in epidermal hyperplasia, accelerated hair follicle morphogenesis and tumor formation. Cancer Res. 2003; 63(3):674-81. View

11.

Chiu C, Monat C, Robitaille M, Lacomme M, Daulat A, MacLeod G . SAPCD2 Controls Spindle Orientation and Asymmetric Divisions by Negatively Regulating the Gαi-LGN-NuMA Ternary Complex. Dev Cell. 2016; 36(1):50-62. DOI: 10.1016/j.devcel.2015.12.016. View

12.

Chalhoub N, Baker S . PTEN and the PI3-kinase pathway in cancer. Annu Rev Pathol. 2008; 4:127-50. PMC: 2710138. DOI: 10.1146/annurev.pathol.4.110807.092311. View

13.

Hehnly H, Canton D, Bucko P, Langeberg L, Ogier L, Gelman I . A mitotic kinase scaffold depleted in testicular seminomas impacts spindle orientation in germ line stem cells. Elife. 2015; 4:e09384. PMC: 4612572. DOI: 10.7554/eLife.09384. View

14.

Ipponjima S, Hibi T, Nemoto T . Three-Dimensional Analysis of Cell Division Orientation in Epidermal Basal Layer Using Intravital Two-Photon Microscopy. PLoS One. 2016; 11(9):e0163199. PMC: 5033459. DOI: 10.1371/journal.pone.0163199. View

15.

Joost S, Annusver K, Jacob T, Sun X, Dalessandri T, Sivan U . The Molecular Anatomy of Mouse Skin during Hair Growth and Rest. Cell Stem Cell. 2020; 26(3):441-457.e7. DOI: 10.1016/j.stem.2020.01.012. View

16.

Trotman L, Niki M, Dotan Z, Koutcher J, Di Cristofano A, Xiao A . Pten dose dictates cancer progression in the prostate. PLoS Biol. 2003; 1(3):E59. PMC: 270016. DOI: 10.1371/journal.pbio.0000059. View

17.

Madisen L, Zwingman T, Sunkin S, Oh S, Zariwala H, Gu H . A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2009; 13(1):133-40. PMC: 2840225. DOI: 10.1038/nn.2467. View

18.

Morrow A, Underwood J, Seldin L, Hinnant T, Lechler T . Regulated spindle orientation buffers tissue growth in the epidermis. Elife. 2019; 8. PMC: 6794086. DOI: 10.7554/eLife.48482. View

19.

Choi B, Xie S, Dai W . PTEN is a negative regulator of mitotic checkpoint complex during the cell cycle. Exp Hematol Oncol. 2017; 6:19. PMC: 5492438. DOI: 10.1186/s40164-017-0079-0. View

20.

di Pietro F, Echard A, Morin X . Regulation of mitotic spindle orientation: an integrated view. EMBO Rep. 2016; 17(8):1106-30. PMC: 4967962. DOI: 10.15252/embr.201642292. View