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https://hdl.handle.net/2440/129528
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dc.contributor.author | Boyle, S.T. | - |
dc.contributor.author | Mittal, P. | - |
dc.contributor.author | Kaur, G. | - |
dc.contributor.author | Hoffmann, P. | - |
dc.contributor.author | Samuel, M.S. | - |
dc.contributor.author | Klingler-Hoffmann, M. | - |
dc.date.issued | 2020 | - |
dc.identifier.citation | Journal of Proteome Research, 2020; 19(10):4093-4103 | - |
dc.identifier.issn | 1535-3893 | - |
dc.identifier.issn | 1535-3907 | - |
dc.identifier.uri | http://hdl.handle.net/2440/129528 | - |
dc.description.abstract | Tumorigenesis involves a complex interplay between genetically modified cancer cells and their adjacent normal tissue, the stroma. We used an established a breast cancer mouse model to investigate this interrelationship. 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 tu-mors 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 (ROC) tool. Peptides were identified by LC-MS/MS 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, corre-lates with cancer progression in two human breast cancer genomic datasets, 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 cancer-associated fibroblasts 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. | - |
dc.description.statementofresponsibility | Sarah T. Boyle, Parul Mittal, Gurjeet Kaur, Peter Hoffmann, Michael S. Samuel, and Manuela Klingler-Hoffmann | - |
dc.language.iso | en | - |
dc.publisher | American Chemical Society | - |
dc.rights | © 2020 American Chemical Society | - |
dc.source.uri | http://dx.doi.org/10.1021/acs.jproteome.0c00511 | - |
dc.subject | MALDI-MSI; breast cancer; Rho-associated protein kinase (ROCK); tumor; stroma; tumor microenvironment; extracellular matrix; collagen | - |
dc.title | Uncovering tumor−stroma inter-relationships using MALDI Mass spectrometry imaging | - |
dc.type | Journal article | - |
dc.identifier.doi | 10.1021/acs.jproteome.0c00511 | - |
dc.relation.grant | NHMRC | - |
pubs.publication-status | Published | - |
dc.identifier.orcid | Samuel, M.S. [0000-0001-7880-6379] | - |
dc.identifier.orcid | Klingler-Hoffmann, M. [0000-0003-2165-7813] | - |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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