Mitogen-activated protein kinase signaling causes malignant melanoma cells to differentially alter extracellular matrix biosynthesis to promote cell survival

BMC Cancer

Research Article

Heather Tillman¹  King Leung Fung²  Benjamin H. Blehm²  Anna Afasizheva²  Wilfred D. Vieira²  Alexus Devine²  Yorihisa Kotobuki²  Kandice Tanner²  Ben Busby³  Emily I. Chen⁴ 

[1] Laboratories of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr., 20892, Bethesda, MD, USA;Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr., 20892, Bethesda, MD, USA;National Centers for Biotechnology Information, National Library of Medicine, National Institutes of Health, 20892, Bethesda, MD, USA;Proteomics Shared Resource at the Herbert Irving Comprehensive Cancer Center & Department of Pharmacology, Columbia University Medical Center, 10032, New York, NY, USA;

关键词: Melanoma;    Fibronectin;    Extracellular matrix;    MAPK;    Integrin;    Tenascin-C;    Vemurafenib;    Dabrafenib;   

DOI  :  10.1186/s12885-016-2211-7

 received in 2015-08-22, accepted in 2016-02-22,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundIntrinsic and acquired resistance to drug therapies remains a challenge for malignant melanoma patients. Intratumoral heterogeneities within the tumor microenvironment contribute additional complexity to the determinants of drug efficacy and acquired resistance.MethodsWe use 3D biomimetic platforms to understand dynamics in extracellular matrix (ECM) biogenesis following pharmaceutical intervention against mitogen-activated protein kinases (MAPK) signaling. We further determined temporal evolution of secreted ECM components by isogenic melanoma cell clones.ResultsWe found that the cell clones differentially secrete and assemble a myriad of ECM molecules into dense fibrillar and globular networks. We show that cells can modulate their ECM biosynthesis in response to external insults. Fibronectin (FN) is one of the key architectural components, modulating the efficacy of a broad spectrum of drug therapies. Stable cell lines engineered to secrete minimal levels of FN showed a concomitant increase in secretion of Tenascin-C and became sensitive to BRAFV600E and ERK inhibition as clonally- derived 3D tumor aggregates. These cells failed to assemble exogenous FN despite maintaining the integrin machinery to facilitate cell- ECM cross-talk. We determined that only clones that increased FN production via p38 MAPK and β1 integrin survived drug treatment.ConclusionsThese data suggest that tumor cells engineer drug resistance by altering their ECM biosynthesis. Therefore, drug treatment may induce ECM biosynthesis, contributing to de novo resistance.

【 授权许可】

CC BY   
© Afasizheva et al. 2016