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Distinct routes to metastasis: plasticity-dependent and plasticity-independent pathways

View Article: PubMed Central - PubMed

ABSTRACT

The cascade that culminates in macrometastases is thought to be mediated by phenotypic plasticity, including epithelial-mesenchymal and mesenchymal-epithelial transitions (EMT and MET). While there is substantial support for the role of EMT in driving cancer cell invasion and dissemination, much less is known about the importance of MET in the later steps of metastatic colonization. We created novel reporters, which integrate transcriptional and post-transcriptional regulation, to test whether MET is required for metastasis in multiple in vivo cancer models. In a model of carcinosarcoma, metastasis occurred via an MET-dependent pathway; however, in two prostate carcinoma models, metastatic colonization was MET-independent. Indeed, the MET-independent pathway was supported by reanalysis of pre-clinical and clinical data. These results provide evidence for both MET-dependent and MET-independent metastatic pathways.

No MeSH data available.


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Lineage tracing suggests that MET is rare during tumorigenesis and metastasisA. Tumors from AT3 cells harboring RG and either pcDNA6, constitutively active Cre, or E-cadCreIIIcI2 express DsRed, EGFP, and a mixture of both fluorescence proteins (white arrows), respectively. Dotted white lines highlight the outer edges of the tumors. Cultured cells from each tumor type are indicated in the right set of panels. A mixture of DsRed-positive and EGFP-positive cells were cultured from tumors harboring the MET reporter, E-cadCreIIIcI2. B. A representative, whole mount image of the lungs, with visible metastases indicated with black arrows. AT3 metastases maintained DsRed expression, with only rare MET-like events, suggesting an MET-independent route to metastasis. C. The percent MET in cultured cells (+ symbol), primary tumors (○ symbol), and lung metastases (□ symbol) was quantified by flow cytometry.
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Figure 3: Lineage tracing suggests that MET is rare during tumorigenesis and metastasisA. Tumors from AT3 cells harboring RG and either pcDNA6, constitutively active Cre, or E-cadCreIIIcI2 express DsRed, EGFP, and a mixture of both fluorescence proteins (white arrows), respectively. Dotted white lines highlight the outer edges of the tumors. Cultured cells from each tumor type are indicated in the right set of panels. A mixture of DsRed-positive and EGFP-positive cells were cultured from tumors harboring the MET reporter, E-cadCreIIIcI2. B. A representative, whole mount image of the lungs, with visible metastases indicated with black arrows. AT3 metastases maintained DsRed expression, with only rare MET-like events, suggesting an MET-independent route to metastasis. C. The percent MET in cultured cells (+ symbol), primary tumors (○ symbol), and lung metastases (□ symbol) was quantified by flow cytometry.

Mentions: The data above suggested that the E-cadCreIIIcI2 reporter could be used to determine the frequency of MET events in tumors. AT3 cells stably transfected with RG and E-cadCreIIIcI2 were injected subcutaneously (s.c.) into the left flanks of male Copenhagen or nude rats. As observed with AT3 cells in culture, primary tumors from cells transfected with pcDNA6 or Cre ORF reporters exclusively expressed DsRed or EGFP, respectively (Figure 3A). Interestingly, tumors from cells harboring RG and E-cadCreIIIcI2 were predominantly DsRed+, but contained multiple foci of EGFP+ cells (Figure 3A; white arrows).


Distinct routes to metastasis: plasticity-dependent and plasticity-independent pathways
Lineage tracing suggests that MET is rare during tumorigenesis and metastasisA. Tumors from AT3 cells harboring RG and either pcDNA6, constitutively active Cre, or E-cadCreIIIcI2 express DsRed, EGFP, and a mixture of both fluorescence proteins (white arrows), respectively. Dotted white lines highlight the outer edges of the tumors. Cultured cells from each tumor type are indicated in the right set of panels. A mixture of DsRed-positive and EGFP-positive cells were cultured from tumors harboring the MET reporter, E-cadCreIIIcI2. B. A representative, whole mount image of the lungs, with visible metastases indicated with black arrows. AT3 metastases maintained DsRed expression, with only rare MET-like events, suggesting an MET-independent route to metastasis. C. The percent MET in cultured cells (+ symbol), primary tumors (○ symbol), and lung metastases (□ symbol) was quantified by flow cytometry.
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Related In: Results  -  Collection

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Figure 3: Lineage tracing suggests that MET is rare during tumorigenesis and metastasisA. Tumors from AT3 cells harboring RG and either pcDNA6, constitutively active Cre, or E-cadCreIIIcI2 express DsRed, EGFP, and a mixture of both fluorescence proteins (white arrows), respectively. Dotted white lines highlight the outer edges of the tumors. Cultured cells from each tumor type are indicated in the right set of panels. A mixture of DsRed-positive and EGFP-positive cells were cultured from tumors harboring the MET reporter, E-cadCreIIIcI2. B. A representative, whole mount image of the lungs, with visible metastases indicated with black arrows. AT3 metastases maintained DsRed expression, with only rare MET-like events, suggesting an MET-independent route to metastasis. C. The percent MET in cultured cells (+ symbol), primary tumors (○ symbol), and lung metastases (□ symbol) was quantified by flow cytometry.
Mentions: The data above suggested that the E-cadCreIIIcI2 reporter could be used to determine the frequency of MET events in tumors. AT3 cells stably transfected with RG and E-cadCreIIIcI2 were injected subcutaneously (s.c.) into the left flanks of male Copenhagen or nude rats. As observed with AT3 cells in culture, primary tumors from cells transfected with pcDNA6 or Cre ORF reporters exclusively expressed DsRed or EGFP, respectively (Figure 3A). Interestingly, tumors from cells harboring RG and E-cadCreIIIcI2 were predominantly DsRed+, but contained multiple foci of EGFP+ cells (Figure 3A; white arrows).

View Article: PubMed Central - PubMed

ABSTRACT

The cascade that culminates in macrometastases is thought to be mediated by phenotypic plasticity, including epithelial-mesenchymal and mesenchymal-epithelial transitions (EMT and MET). While there is substantial support for the role of EMT in driving cancer cell invasion and dissemination, much less is known about the importance of MET in the later steps of metastatic colonization. We created novel reporters, which integrate transcriptional and post-transcriptional regulation, to test whether MET is required for metastasis in multiple in vivo cancer models. In a model of carcinosarcoma, metastasis occurred via an MET-dependent pathway; however, in two prostate carcinoma models, metastatic colonization was MET-independent. Indeed, the MET-independent pathway was supported by reanalysis of pre-clinical and clinical data. These results provide evidence for both MET-dependent and MET-independent metastatic pathways.

No MeSH data available.


Related in: MedlinePlus