Dataset Information

Targeting DDR1 and DDR2 overcomes matrix-mediated melanoma cell adaptation to BRAF-targeted therapy

ABSTRACT: To investigate the contribution of fibroblast-derived extracellular matrices (ECMs) to the resistance to targeted therapies in BRAF-mutated melanoma cells, we generated native-like 3D ECMs from human primary fibroblasts obtained from healthy individuals or melanoma patients. Cell-derived matrices from human dermal fibroblasts (HDF), skin melanoma associated fibroblasts (MAF) and two different lymph node fibroblast reticular cells (FRC) were denuded of cells and their composition was analyzed by mass spectrometry.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Fibroblast

DISEASE(S): Skin Cancer

SUBMITTER: AUDEBERT Stephane

LAB HEAD: Deckert Marcel

PROVIDER: PXD026645 | Pride | 2021-11-12

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	Garlau_Rep1.raw	Raw
	Garlau_Rep1_180830201633.raw	Raw
	Garlau_Rep1_180830225548.raw	Raw
	Garlau_Rep2_180903003222.raw	Raw
	Garlau_Rep2_180903031139.raw	Raw

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Publications

Targeting Discoidin Domain Receptors DDR1 and DDR2 overcomes matrix-mediated tumor cell adaptation and tolerance to BRAF-targeted therapy in melanoma.

Berestjuk Ilona I Lecacheur Margaux M Carminati Alexandrine A Diazzi Serena S Rovera Christopher C Prod'homme Virginie V Ohanna Mickael M Popovic Ana A Mallavialle Aude A Larbret Frédéric F Pisano Sabrina S Audebert Stéphane S Passeron Thierry T Gaggioli Cédric C Girard Christophe A CA Deckert Marcel M Tartare-Deckert Sophie S

EMBO molecular medicine 20211227 2

Resistance to BRAF/MEK inhibitor therapy in BRAF<sup>V600</sup> -mutated advanced melanoma remains a major obstacle that limits patient benefit. Microenvironment components including the extracellular matrix (ECM) can support tumor cell adaptation and tolerance to targeted therapy; however, the underlying mechanisms remain poorly understood. Here, we investigated the process of matrix-mediated drug resistance (MMDR) in response to BRAF<sup>V600</sup> pathway inhibition in melanoma. We demonstrat ...[more]

PMID: 34957688

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Project description:The fibroblast-populated 3D collagen matrix has been used to study the effect of mechanical stress on cell fate; this process is relevant to the fields of wound healing and tissue engineering. Gene array data was generated from mechanically stressed vs. stress-released matrices. The parameters of the collagen matrix model were: collagen type = bovine type I; collagen concentration = 1.5 mg/mL; initial matrix volume = 0.2 mL; initial matrix diameter = 11 mm (cultured in 24-well plates); cell type = human foreskin fibroblast, passage <10; initial matrix cell concentration = 1,000,000 cell/mL (200,000 cell/matrix); culture medium = 5% FBS in DMEM with 1 M-BM-5g/mL ascorbate. Matrices (n = 6 per experimental group) were incubated for 24 hr in the attached state; the released groups then underwent matrix detachment from the culture plate (defined as t = 0), while the attached groups were left undisturbed. RNA was isolated from attached and released matrices 6 and 24 hr after t = 0. Gene expression in the attached vs. released condition at 6 or 24 hr then was analyzed by hybridizing the anti-sense RNA derived from attached and released matrices at a given time point onto a single chip. Refer to the attached Figure 1 for the experimental design. The index experiment was defined as the comparison of gene expression in attached vs. released collagen matrices in a single strain of human foreskin fibroblasts at 6 and 24 hr after stress-release (i.e., after t = 0). Each experiment utilized two mechanical conditions (attached and released) at two time points (6 and 24 hr). So with each condition utilizing 6 matrices, each index experiment required a total of 24 matrices. In each index experiment, the chip hybridizations were: (i) 6 hr attached vs. 6 hr released, and (ii) 24 hr attached vs. 24 hr released (i.e., two gene chips per index experiment). Each hybridization was done using a 10K spotted gene chip manufactured in the UNMC Microarray Core Facility. The index experiment was performed on three fibroblast strains, meaning that expressional data was derived from three foreskin donors (nonpooled samples). Dye-swap was not performed; dye assigned to attached vs. released remained constant among all chips. Since the index experiment was performed three times, the total number of gene chips used for this entire dataset was six.