An Arntl2-Driven Secretome Enables Lung Adenocarcinoma Metastatic Self-Sufficiency

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2016 May 7

PMID 27150038

Citations 58

Authors

Jennifer J Brady

Chen-Hua Chuang

Peyton G Greenside

Zoe N Rogers

Christopher W Murray

Deborah R Caswell

Ursula Hartmann

Andrew J Connolly

E Alejandro Sweet-Cordero

Anshul Kundaje

Monte M Winslow

Affiliations

Soon will be listed here.

Abstract

The ability of cancer cells to establish lethal metastatic lesions requires the survival and expansion of single cancer cells at distant sites. The factors controlling the clonal growth ability of individual cancer cells remain poorly understood. Here, we show that high expression of the transcription factor ARNTL2 predicts poor lung adenocarcinoma patient outcome. Arntl2 is required for metastatic ability in vivo and clonal growth in cell culture. Arntl2 drives metastatic self-sufficiency by orchestrating the expression of a complex pro-metastatic secretome. We identify Clock as an Arntl2 partner and functionally validate the matricellular protein Smoc2 as a pro-metastatic secreted factor. These findings shed light on the molecular mechanisms that enable single cancer cells to form allochthonous tumors in foreign tissue environments.

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References

Schoenhard J, Eren M, Johnson C, Vaughan D . Alternative splicing yields novel BMAL2 variants: tissue distribution and functional characterization. Am J Physiol Cell Physiol. 2002; 283(1):C103-14. DOI: 10.1152/ajpcell.00541.2001. View

Weeraratna A, Jiang Y, Hostetter G, Rosenblatt K, Duray P, Bittner M . Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma. Cancer Cell. 2002; 1(3):279-88. DOI: 10.1016/s1535-6108(02)00045-4. View

Fidler I . The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nat Rev Cancer. 2003; 3(6):453-8. DOI: 10.1038/nrc1098. View

Kang Y, Siegel P, Shu W, Drobnjak M, Kakonen S, Cordon-Cardo C . A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003; 3(6):537-49. DOI: 10.1016/s1535-6108(03)00132-6. View

De S, Chen J, Narizhneva N, Heston W, Brainard J, Sage E . Molecular pathway for cancer metastasis to bone. J Biol Chem. 2003; 278(40):39044-50. PMC: 1459419. DOI: 10.1074/jbc.M304494200. View

Lu Z, Ghosh S, Wang Z, Hunter T . Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion. Cancer Cell. 2004; 4(6):499-515. DOI: 10.1016/s1535-6108(03)00304-0. View

SAGE H, Vernon R, Funk S, Everitt E, Angello J . SPARC, a secreted protein associated with cellular proliferation, inhibits cell spreading in vitro and exhibits Ca+2-dependent binding to the extracellular matrix. J Cell Biol. 1989; 109(1):341-56. PMC: 2115491. DOI: 10.1083/jcb.109.1.341. View

Kimura S, Hara Y, Pineau T, Fox C, Ward J, Gonzalez F . The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev. 1996; 10(1):60-9. DOI: 10.1101/gad.10.1.60. View

Bafico A, Liu G, Goldin L, Harris V, Aaronson S . An autocrine mechanism for constitutive Wnt pathway activation in human cancer cells. Cancer Cell. 2004; 6(5):497-506. DOI: 10.1016/j.ccr.2004.09.032. View

10.

Jackson E, Olive K, Tuveson D, Bronson R, Crowley D, Brown M . The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 2005; 65(22):10280-8. DOI: 10.1158/0008-5472.CAN-05-2193. View

11.

Rocnik E, Liu P, Sato K, Walsh K, Vaziri C . The novel SPARC family member SMOC-2 potentiates angiogenic growth factor activity. J Biol Chem. 2006; 281(32):22855-64. DOI: 10.1074/jbc.M513463200. View

12.

Maier S, Paulsson M, Hartmann U . The widely expressed extracellular matrix protein SMOC-2 promotes keratinocyte attachment and migration. Exp Cell Res. 2008; 314(13):2477-87. DOI: 10.1016/j.yexcr.2008.05.020. View

13.

Shedden K, Taylor J, Enkemann S, Tsao M, Yeatman T, Gerald W . Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study. Nat Med. 2008; 14(8):822-7. PMC: 2667337. DOI: 10.1038/nm.1790. View

14.

Nguyen D, Bos P, Massague J . Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009; 9(4):274-84. DOI: 10.1038/nrc2622. View

15.

Nguyen D, Chiang A, Zhang X, Kim J, Kris M, Ladanyi M . WNT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis. Cell. 2009; 138(1):51-62. PMC: 2742946. DOI: 10.1016/j.cell.2009.04.030. View

16.

Sasaki M, Yoshitane H, Du N, Okano T, Fukada Y . Preferential inhibition of BMAL2-CLOCK activity by PER2 reemphasizes its negative role and a positive role of BMAL2 in the circadian transcription. J Biol Chem. 2009; 284(37):25149-59. PMC: 2757218. DOI: 10.1074/jbc.M109.040758. View

17.

Desgrosellier J, Cheresh D . Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2009; 10(1):9-22. PMC: 4383089. DOI: 10.1038/nrc2748. View

18.

Shi S, Hida A, McGuinness O, Wasserman D, Yamazaki S, Johnson C . Circadian clock gene Bmal1 is not essential; functional replacement with its paralog, Bmal2. Curr Biol. 2010; 20(4):316-21. PMC: 2907674. DOI: 10.1016/j.cub.2009.12.034. View

19.

Prowse A, Chong F, Gray P, Munro T . Stem cell integrins: implications for ex-vivo culture and cellular therapies. Stem Cell Res. 2010; 6(1):1-12. DOI: 10.1016/j.scr.2010.09.005. View

20.

Winslow M, Dayton T, Verhaak R, Kim-Kiselak C, Snyder E, Feldser D . Suppression of lung adenocarcinoma progression by Nkx2-1. Nature. 2011; 473(7345):101-4. PMC: 3088778. DOI: 10.1038/nature09881. View