The macrophage-stimulating protein pathway promotes metastasis in a mouse model for breast cancer and predicts poor prognosis in humans

Welm, Alana L.; Sneddon, Julie B.; Taylor, Carmen; Nuyten, Dimitry S.A.; Vijver, Marc J. van de; Hasegawa, B.H.; Bishop, J. Michael

doi:10.1073/pnas.0702095104

Cited by 134 publications

(155 citation statements)

References 37 publications

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“…Tumor cells were derived from spontaneous tumors arising in transgenic FVB MMTV-PyMT mice, and were engineered to express mouse MSP and the NP118 immunodominant peptide through retroviral transduction and subsequent positive selection with 5 μg/ml puromycin (PyMT-NP cells). Tumor cells were cultured in DME:F12 medium (Gibco, Invitrogen) supplemented with fetal bovine serum (10%) (Gibco, Invitrogen), insulin-transferrin-selenium-ethanolamine (1x) (Gibco, Invitrogen), recombinant murine EGF (10 ng/ml) (Invitrogen), hydrocortisone (1 μg/ml) (Sigma), penicillin-streptomycin-gentamycin (Gibco, Invitrogen) (1x) for a maximum of 4 days using previously described methods 16,34 prior to injection into mice. MC38 colon carcinoma cells were purchased from Kerafast (Boston, USA), and maintained in Dulbecco’s Modified Eagle Medium (DMEM) containing high glucose and GlutaMAX (Gibco), supplemented with heat-inactivated fetal bovine serum (10%), nonessential amino acids (0.1 mM), sodium pyruvate (1 mM), penicillin/streptomycin (100 U/ml), gentamycin (50 mg/ml) and HEPES (10 mM).…”

Section: Methodsmentioning

confidence: 99%

“…25–28 Particularly, overexpression of RON in breast tumors is associated with increased metastasis and poor clinical outcomes. 16,26 In macrophages, activation of RON by MSP results in attenuation of immune responses. 29–33 Previously, we and others have shown that host RON signaling negatively regulates antitumor immunity in mouse models of cancer.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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“…Given this and the data supporting MT-SP1, MSP-1, and RON expression in various cancer tissues, we suggest that this pathway may be important in tumor development, maintenance, and/or progression. MT-SP1, MSP-1, and RON have all been established as cancerassociated molecules (2,17,33,34). We suggest that cancer cells may ''hijack'' this signaling pathway by increasing coordinate expression of MT-SP1, MSP-1, and RON to drive proliferation and migration, two fundamental traits of transformed cells.…”

mentioning

confidence: 99%

Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway

Bhatt

Welm

Farady

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

114

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A multidisciplinary method combining transcriptional data, specificity profiling, and biological characterization of an enzyme may be used to predict novel substrates. By integrating protease substrate profiling with microarray gene coexpression data from nearly 2,000 human normal and cancerous tissue samples, three fundamental components of a protease-activated signaling pathway were identified. We find that MT-SP1 mediates extracellular signaling by regulating the local activation of the prometastatic growth factor MSP-1. We demonstrate MT-SP1 expression in peritoneal macrophages, and biochemical methods confirm the ability of MT-SP1 to cleave and activate pro-MSP-1 in vitro and in a cellular context. MT-SP1 induced the ability of MSP-1 to inhibit nitric oxide production in bone marrow macrophages. Addition of HAI-1 or an MT-SP1-specific antibody inhibitor blocked the proteolytic activation of MSP-1 at the cell surface of peritoneal macrophages. Taken together, our work indicates that MT-SP1 is sufficient for MSP-1 activation and that MT-SP1, MSP-1, and the previously shown MSP-1 tyrosine kinase receptor RON are required for peritoneal macrophage activation. This work shows that this triad of growth factor, growth factor activator protease, and growth factor receptor is a protease-activated signaling pathway. Individually, MT-SP1 and RON overexpression have been implicated in cancer progression and metastasis. Transcriptional coexpression of these genes suggests that this signaling pathway may be involved in several human cancers.cancer ͉ macrophage activation ͉ protease substrate specificity ͉ proteomics D espite the successful physiological and biochemical characterization of many proteases, the vast majority of the Ͼ2% of the human genome that encodes proteases has yet to be functionally classified. Although many approaches demonstrate the sufficiency of a protease to cleave a given substrate, very few are able to address the physiological relevance of such in vitro findings. Cell-surface proteolysis is suggested to play a major role in cancer progression and metastasis through the processing of macromolecules important for regulating the extracellular environment. The cell-surface localization, high activity, and exquisite specificity of type II transmembrane serine proteases (TTSPs) suggest a role in outside-in signaling and interaction with the microenvironment. We elected to apply a multifaceted approach to identify physiologically relevant substrates of one prominent member of this family, membrane type serine protease 1 (MT-SP1/matriptase).Members of the TTSP family, such as hepsin and MT-SP1, are highly expressed in many cancers, including those of the prostate, breast, colon, and ovary (1-9). Both overexpression and inhibition studies have supported the role of MT-SP1 in tumorigenesis and tumor growth. Targeted overexpression of MT-SP1 in squamous epithelia in mice results in skin-limited nodules of squamous cell carcinoma that become metastatic in the presence of the chemical carcinogen DMBA (10). ...

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“…Finally, a large number of genes involved in tumour invasion were underexpressed in non-nodal MCL: PGF, which enhances angiogenesis (Autiero et al, 2003;: Luttun et al, 2002); ST14, whose expression has been associated with breast, colon, prostate and ovarian tumours, and has a role in cancer invasion and metastasis (Uhland, 2006;Welm et al, 2007;Warren et al, 2009); ETS1, which is involved in breast cancer progression and melanoma cell spread (Keehn et al, 2003;Turner et al, 2007); OCIAD1, which is overexpressed in metastatic ovarian cancer (Sengupta et al, 2008). Overall, the downmodulation of these gene categories could help to explain the absence of nodal involvement in these cases, providing possible valuable markers that could be explored by immunohistochemistry in an independent series.…”

Section: P-valuementioning

confidence: 99%

Behind the scenes of non‐nodal MCL: downmodulation of genes involved in actin cytoskeleton organization, cell projection, cell adhesion, tumour invasion, TP53 pathway and mutated status of immunoglobulin heavy chain genes

et al. 2011

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SummaryMantle cell lymphoma (MCL) is an aggressive neoplasm with a short survival. Cases with leukaemic MCL and splenomegaly without adenopathies (non‐nodal MCL) may have a more indolent course. To gain insights into the biological features underlying this presentation, we investigated the gene expression profile (GEP) and the IGHV mutational status in a cohort of leukaemic MCL cases. Comparison of MCL with other lymphoproliferative disorders (i.e. splenic marginal zone lymphoma, follicular lymphoma, chronic lymphocytic leukaemia) revealed a MCL signature enriched for the following gene categories: mitochondrion, oxidoreductase activity, response to stress, to DNA damage and TP53‐pathway. Furthermore, GEP analysis revealed that non‐nodal MCL cases were characterized by the down‐modulation of the following gene categories: cell projection, actin cytoskeleton organization, cell adhesion (ITGAE, CELSR1, PCDH9) and tumour invasion/progression (PGF, ST14, ETS1, OCIAD1, EZR). Many down‐modulated genes were related to the TP53‐pathway and to DNA damage response. IGHV status proved unmutated in all nodal and mutated in all non‐nodal MCL. Non‐nodal leukaemic MCLs display a peculiar clinical presentation, with distinctive biological features, such as mutated IGHV and a transcriptional profile lacking tumour invasion properties, that might contribute to the absence of nodal involvement and to the less aggressive clinical course.

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The macrophage-stimulating protein pathway promotes metastasis in a mouse model for breast cancer and predicts poor prognosis in humans

Cited by 134 publications

References 37 publications

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Coordinate expression and functional profiling identify an extracellular proteolytic signaling pathway

Behind the scenes of non‐nodal MCL: downmodulation of genes involved in actin cytoskeleton organization, cell projection, cell adhesion, tumour invasion, TP53 pathway and mutated status of immunoglobulin heavy chain genes

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