Extracellular Matrix Receptor Expression in Subtypes of Lung Adenocarcinoma Potentiates Outgrowth of Micrometastases

Overview

Journal Cancer Res

Specialty Oncology

Date 2017 Feb 16

PMID 28196904

Citations 45

Authors

Laura E Stevens

William K C Cheung

Sally J Adua

Anna Arnal-Estape

Minghui Zhao

Zongzhi Liu

Kelly Brewer

Roy S Herbst

Don X Nguyen

Affiliations

Soon will be listed here.

Abstract

Mechanisms underlying the propensity of latent lung adenocarcinoma (LUAD) to relapse are poorly understood. In this study, we show how differential expression of a network of extracellular matrix (ECM) molecules and their interacting proteins contributes to risk of relapse in distinct LUAD subtypes. Overexpression of the hyaluronan receptor HMMR in primary LUAD was associated with an inflammatory molecular signature and poor prognosis. Attenuating HMMR in LUAD cells diminished their ability to initiate lung tumors and distant metastases. HMMR upregulation was not required for dissemination , but enhanced ECM-mediated signaling, LUAD cell survival, and micrometastasis expansion in hyaluronan-rich microenvironments in the lung and brain metastatic niches. Our findings reveal an important mechanism by which disseminated cancer cells can coopt the inflammatory ECM to persist, leading to brain metastatic outgrowths. .

Citing Articles

Molecular Underpinnings of Brain Metastases.

Jacome M, Wu Q, Chen J, Mohamed Z, Mokhtari S, Pina Y Int J Mol Sci. 2025; 26(5).

PMID: 40076927 PMC: 11900073. DOI: 10.3390/ijms26052307.

Breaking boundaries: role of the brain barriers in metastatic process.

Izadi N, Solar P, Hasanova K, Zamani A, Akbar M, Mrazova K Fluids Barriers CNS. 2025; 22(1):3.

PMID: 39780275 PMC: 11708195. DOI: 10.1186/s12987-025-00618-z.

Small cell lung cancer with liver metastases: from underlying mechanisms to treatment strategies.

Fan L, Lin Y, Fu Y, Wang J Cancer Metastasis Rev. 2024; 44(1):5.

PMID: 39585433 DOI: 10.1007/s10555-024-10220-8.

SNAI2 as a Prognostic Biomarker Based on Cancer-Associated Fibroblasts in Patients With Lung Adenocarcinoma.

Li T, Hao Q, Teng Z, Liu Y, Wu J, Zhang J Clin Med Insights Oncol. 2024; 18:11795549241280506.

PMID: 39314798 PMC: 11418231. DOI: 10.1177/11795549241280506.

FOXM1 mediates methotrexate resistance in osteosarcoma cells by promoting autophagy.

Wang L, Zhai D, Tang L, Zhang H, Wang X, Ma N Acta Biochim Biophys Sin (Shanghai). 2024; 56(9):1289-1299.

PMID: 39086352 PMC: 11532242. DOI: 10.3724/abbs.2024084.

References

Kasinski A, Slack F . miRNA-34 prevents cancer initiation and progression in a therapeutically resistant K-ras and p53-induced mouse model of lung adenocarcinoma. Cancer Res. 2012; 72(21):5576-87. PMC: 3488137. DOI: 10.1158/0008-5472.CAN-12-2001. View

Ghajar C, Peinado H, Mori H, Matei I, Evason K, Brazier H . The perivascular niche regulates breast tumour dormancy. Nat Cell Biol. 2013; 15(7):807-17. PMC: 3826912. DOI: 10.1038/ncb2767. View

Quail D, Joyce J . Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013; 19(11):1423-37. PMC: 3954707. DOI: 10.1038/nm.3394. View

Zhang K, Rekhter M, Gordon D, Phan S . Myofibroblasts and their role in lung collagen gene expression during pulmonary fibrosis. A combined immunohistochemical and in situ hybridization study. Am J Pathol. 1994; 145(1):114-25. PMC: 1887314. View

Reticker-Flynn N, Malta D, Winslow M, Lamar J, Xu M, Underhill G . A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis. Nat Commun. 2012; 3:1122. PMC: 3794716. DOI: 10.1038/ncomms2128. View

Petrey A, de la Motte C . Hyaluronan, a crucial regulator of inflammation. Front Immunol. 2014; 5:101. PMC: 3949149. DOI: 10.3389/fimmu.2014.00101. View

Liang J, Jiang D, Noble P . Hyaluronan as a therapeutic target in human diseases. Adv Drug Deliv Rev. 2015; 97:186-203. PMC: 4753080. DOI: 10.1016/j.addr.2015.10.017. View

Goldman S, Chen Z . Perivascular instruction of cell genesis and fate in the adult brain. Nat Neurosci. 2011; 14(11):1382-9. PMC: 3655803. DOI: 10.1038/nn.2963. View

Provenzano P, Cuevas C, Chang A, Goel V, Von Hoff D, Hingorani S . Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012; 21(3):418-29. PMC: 3371414. DOI: 10.1016/j.ccr.2012.01.007. View

10.

Hynes R . Stretching the boundaries of extracellular matrix research. Nat Rev Mol Cell Biol. 2015; 15(12):761-3. DOI: 10.1038/nrm3908. View

11.

Singleton P . Hyaluronan regulation of endothelial barrier function in cancer. Adv Cancer Res. 2014; 123:191-209. PMC: 4470488. DOI: 10.1016/B978-0-12-800092-2.00007-1. View

12.

Arenberg D, Luckhardt T, Carskadon S, Zhao L, Amin M, Koch A . Macrophage migration inhibitory factor promotes tumor growth in the context of lung injury and repair. Am J Respir Crit Care Med. 2010; 182(8):1030-7. PMC: 2970845. DOI: 10.1164/rccm.201001-0120OC. View

13.

Schwertfeger K, Cowman M, Telmer P, Turley E, McCarthy J . Hyaluronan, Inflammation, and Breast Cancer Progression. Front Immunol. 2015; 6:236. PMC: 4459097. DOI: 10.3389/fimmu.2015.00236. View

14.

Hall C, Yang B, Yang X, Zhang S, Turley M, Samuel S . Overexpression of the hyaluronan receptor RHAMM is transforming and is also required for H-ras transformation. Cell. 1995; 82(1):19-26. DOI: 10.1016/0092-8674(95)90048-9. View

15.

Bonnans C, Chou J, Werb Z . Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 2014; 15(12):786-801. PMC: 4316204. DOI: 10.1038/nrm3904. View

16.

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

17.

Valiente M, Obenauf A, Jin X, Chen Q, Zhang X, Lee D . Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell. 2014; 156(5):1002-16. PMC: 3988473. DOI: 10.1016/j.cell.2014.01.040. View

18.

Lennon F, Singleton P . Role of hyaluronan and hyaluronan-binding proteins in lung pathobiology. Am J Physiol Lung Cell Mol Physiol. 2011; 301(2):L137-47. PMC: 3154626. DOI: 10.1152/ajplung.00071.2010. View

19.

Cowman M, Lee H, Schwertfeger K, McCarthy J, Turley E . The Content and Size of Hyaluronan in Biological Fluids and Tissues. Front Immunol. 2015; 6:261. PMC: 4451640. DOI: 10.3389/fimmu.2015.00261. View

20.

Lin J, Jandial R, Nesbit A, Badie B, Chen M . Current and emerging treatments for brain metastases. Oncology (Williston Park). 2015; 29(4):250-7. View