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Tytuł pozycji:

Uncovering Tumor-Stroma Inter-relationships Using MALDI Mass Spectrometry Imaging.

Tytuł:
Uncovering Tumor-Stroma Inter-relationships Using MALDI Mass Spectrometry Imaging.
Autorzy:
Boyle ST; Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide SA 5000, Australia.
Mittal P; Future Industries Institute, University of South Australia, Mawson Lakes SA 5095, Australia.
Kaur G; Institute for Research in Molecular Medicine, Universiti Sains Malaysia, Minden 11800 Pulau Pinang, Malaysia.
Hoffmann P; Future Industries Institute, University of South Australia, Mawson Lakes SA 5095, Australia.
Samuel MS; Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide SA 5000, Australia.; Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide SA 5000, Australia.
Klingler-Hoffmann M; Future Industries Institute, University of South Australia, Mawson Lakes SA 5095, Australia.
Źródło:
Journal of proteome research [J Proteome Res] 2020 Oct 02; Vol. 19 (10), pp. 4093-4103. Date of Electronic Publication: 2020 Sep 16.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Original Publication: Washington, D.C. : American Chemical Society, c2002-
MeSH Terms:
Cancer-Associated Fibroblasts*
Proteomics*
Animals ; Extracellular Matrix ; Fibroblasts ; Humans ; Mice ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; rab GTP-Binding Proteins
Contributed Indexing:
Keywords: MALDI-MSI; Rho-associated protein kinase (ROCK); breast cancer; collagen; extracellular matrix; stroma; tumor; tumor microenvironment
Substance Nomenclature:
EC 3.6.1.- (Rab14 protein, human)
EC 3.6.5.2 (rab GTP-Binding Proteins)
Entry Date(s):
Date Created: 20200902 Date Completed: 20210617 Latest Revision: 20210617
Update Code:
20240104
DOI:
10.1021/acs.jproteome.0c00511
PMID:
32870688
Czasopismo naukowe
Tumorigenesis involves a complex interplay between genetically modified cancer cells and their adjacent normal tissue, the stroma. We used an established breast cancer mouse model to investigate this inter-relationship. Conditional activation of Rho-associated protein kinase (ROCK) in a model of mammary tumorigenesis enhances tumor growth and progression by educating the stroma and enhancing the production and remodeling of the extracellular matrix. We used peptide matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) to quantify the proteomic changes occurring within tumors and their stroma in their regular spatial context. Peptides were ranked according to their ability to discriminate between the two groups, using a receiver operating characteristic tool. Peptides were identified by liquid chromatography tandem mass spectrometry, and protein expression was validated by quantitative immunofluorescence using an independent set of tumor samples. We have identified and validated four key proteins upregulated in ROCK-activated mammary tumors relative to those expressing kinase-dead ROCK, namely, collagen I, α-SMA, Rab14, and tubulin-β4. Rab14 and tubulin-β4 are expressed within tumor cells, whereas collagen I is localized within the stroma. α-SMA is predominantly localized within the stroma but is also expressed at higher levels in the epithelia of ROCK-activated tumors. High expression of COL1A , the gene encoding the pro-α 1 chain of collagen, correlates with cancer progression in two human breast cancer genomic data sets, and high expression of COL1A and ACTA2 (the gene encoding α-SMA) are associated with a low survival probability ( COLIA , p = 0.00013; ACTA2 , p = 0.0076) in estrogen receptor-negative breast cancer patients. To investigate whether ROCK-activated tumor cells cause stromal cancer-associated fibroblasts (CAFs) to upregulate expression of collagen I and α-SMA, we treated CAFs with medium conditioned by primary mammary tumor cells in which ROCK had been activated. This led to abundant production of both proteins in CAFs, clearly highlighting the inter-relationship between tumor cells and CAFs and identifying CAFs as the potential source of high levels of collagen 1 and α-SMA and associated enhancement of tissue stiffness. Our research emphasizes the capacity of MALDI-MSI to quantitatively assess tumor-stroma inter-relationships and to identify potential prognostic factors for cancer progression in human patients, using sophisticated mouse cancer models.

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