title: Mitogen-activated protein kinase signaling causes malignant melanoma cells to differentially alter extracellular matrix biosynthesis to promote cell survival.
abstract: BACKGROUND
  Intrinsic 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  We 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 BRAF(V600E) 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.
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr., Bethesda, MD, 20892, USA. anyarus@gmail.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Afasizheva
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr., Bethesda, MD, 20892, USA. alexus.devine@nih.gov.
authors.forename: Alexus
authors.initials: A
authors.lastname: Devine
authors.affiliation: Laboratories of Genitourinary Cancer Pathogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr., Bethesda, 20892, MD, USA. heather.tillman@nih.gov.
authors.forename: Heather
authors.initials: H
authors.lastname: Tillman
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr., Bethesda, MD, 20892, USA. fungk@nih.gov.
authors.forename: King Leung
authors.initials: KL
authors.lastname: Fung
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr., Bethesda, MD, 20892, USA. vieiraw@pop.nci.nih.gov.
authors.forename: Wilfred D
authors.initials: WD
authors.lastname: Vieira
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr., Bethesda, MD, 20892, USA. benblehm@gmail.com.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Blehm
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr., Bethesda, MD, 20892, USA. yorihisa8986@yahoo.co.jp.
authors.forename: Yorihisa
authors.initials: Y
authors.lastname: Kotobuki
authors.affiliation: National Centers for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, 20892, MD, USA. ben.busby@gmail.com.
authors.forename: Ben
authors.initials: B
authors.lastname: Busby
authors.affiliation: Proteomics Shared Resource at the Herbert Irving Comprehensive Cancer Center & Department of Pharmacology, Columbia University Medical Center, New York, 10032, NY, USA. ec2974@icg.cpmc.columbia.edu.
authors.forename: Emily I
authors.initials: EI
authors.lastname: Chen
authors.affiliation: Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr., Bethesda, MD, 20892, USA. kandice.tanner@nih.gov.
authors.forename: Kandice
authors.initials: K
authors.lastname: Tanner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002465:Cell Movement; D002470:Cell Survival; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005109:Extracellular Matrix / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction; D019063:Tenascin / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D047428:Protein Kinase Inhibitors; D019063:Tenascin; D020928:Mitogen-Activated Protein Kinases