Prometastatic Effect of ATX Derived from Alveolar Type II Pneumocytes and B16-F10 Melanoma Cells
<p>In vitro characterization of Sftpc-WT and Sftpc-KO mice. (<b>A</b>) Agarose electrophoresis of PCR-amplified Enpp2 allele of ATII cells isolated from Sftpc-WT (lanes 1 and 2) and Sftpc-KO (lanes 3 and 4) mice, treated in vivo with TAM (100 mg/kg/day for 5 days). The size of the Enpp2 WT allele is 441 bp, Enpp2 floxed allele is 540 bp, and Enpp2 deleted allele is 370 bp. The PCR product from ATII cells isolated from Sftpc-WT mouse showed a band corresponding to Enpp2 WT allele (lane 1) and no Enpp2 deleted allele was detected (lane 2). In contrast, ATII cells isolated from Sftpc-KO mouse showed a floxed allele (lane 3) and a deleted Enpp2 allele (lane 4). (<b>B</b>) WB analysis of cell lysates from ATII cells from Sftpc-WT mice (lane 2) and Sftpc-KO mice (lane 3) treated with TAM. Recombinant ATX (rATX, lane 1) was used as a positive control. Two weeks post-TAM treatment, ATII cells were isolated from Sftpc-WT and Sftpc-KO mice and put in culture for 5 days. Eighteen hours prior to lysate being harvested, cells were cultured in serum-free medium + 10 ng/mL of TNFα, in order to stimulate ATX production. One hundred fifty micrograms of protein was loaded into an 8% SDS-PAGE. A ~100 kDa band corresponding to ATX can be observed. Graph of the densitograms represents the percent of ATX band intensity normalized to the WT. ATII cells isolated from Sftpc-KO mice show a 90% decrease in band intensity (mean ± SD of 3 independent experiments). (<b>C</b>) Representative images of H&E stained 5 μm lung sections from TAM-treated naïve Sftpc-WT (<b>left</b>) and Sftpc-KO (<b>right</b>) and corn-oil-treated control (<b>lower</b> panel) mice. There was no sign of major histopathological lesion observed between the three different cohorts of lungs. Lungs were harvested two weeks post-TAM treatment, inflated with 10% formalin, fixed, and sectioned. Scale bars represent 100 μm (10× magnification).</p> "> Figure 2
<p>ATX derived from B16-F10 partially controls the progression of lung metastasis. (<b>A</b>) Western blot analysis of cell lysates performed in two technical repeats of WT B16-F10 cells (lanes 1 and 2, respectively) and ATX-KO B16-F10 cells (lanes 3 and 4, respectively). Recombinant ATX (rATX, lane 6) was used as a positive control. Densitometric quantification of the ATX band showed an average 91% decrease in ATX expression in ATX-KO B16-F10 cell lysate compared to WT B16-F10 cells (mean ± SD of 4 independent experiments). Cell lines were cultured for 18 h in serum-free medium before lysates were harvested. One hundred micrograms of protein was loaded into an 8% SDS-PAGE. (<b>B</b>) ATX immunofluorescence staining in WT and ATX-KO B16-F10 cells. Cells were stained for ATX (green) using the 4F1 antibody at 1:100 dilution, with DAPI nuclear counterstain (1:5000). Upper panels show the staining of WT B16-F10 cells, whereas lower panels show the staining of ATX-KO B16-F10 cells. Scale bars represent 100 μm (20× magnification). (<b>C</b>) Quantification of ATX activity in concentrated conditioned medium (CCM) from WT and ATX-KO B16-F10. Crosshatched bar represents 10 nM recombinant ATX (rATX) positive control, white bar corresponds to the ATX activity in the CCM of WT B16-F10 cells (<span class="html-italic">n</span> = 5), and gray bar is the activity measured in CCM of ATX-KO B16-F10 cells (<span class="html-italic">n</span> = 5). ATX-KO B16-F10 cells present a 74.3% decrease in ATX activity compared to WT B16-F10 cells (Mann–Whitney, ** <span class="html-italic">p</span> = 0.0079). (<b>D</b>) Comparison of the growth rate between WT (black) and ATX-KO (red) B16-F10 performed in six replicates; representative of three independent experiments. (<b>E</b>) Metastatic foci in the lungs of C57BL/6 mice inoculated with 1 × 10<sup>5</sup> WT B16-F10 cells (white bar, <span class="html-italic">n</span> = 18) or ATX-KO B16-F10 cells (gray bar, <span class="html-italic">n</span> = 20), and representative lung pictures from this experiment (below). Mice inoculated with ATX-KO B16-F10 cells showed a 34% decrease in lung metastases (unpaired <span class="html-italic">t</span>-test, * <span class="html-italic">p</span> = 0.04, data from 2 independent experiments).</p> "> Figure 3
<p>Only combined KO of ATX in B16-F10 cells and ATII cells decreases lung metastasis burden compared to KO in ATII cells alone. (<b>A</b>) Metastatic nodules in the lungs of Sftpc-WT (white bar, <span class="html-italic">n</span> = 16) and Sftpc-KO (gray bar, <span class="html-italic">n</span> = 23) mice inoculated with 1.5 × 10<sup>5</sup> ATX-KO B16-F10 cells. Sftpc-KO mice showed a 30% decrease in metastatic nodules (unpaired <span class="html-italic">t</span>-test, * <span class="html-italic">p</span> = 0.028 from 2 independent experiments). (<b>B</b>) ATX activity in the BALF from Sftpc-WT (white bar, <span class="html-italic">n</span> = 6) and Sftpc-KO (gray bar, <span class="html-italic">n</span> = 14) mice inoculated with 1.5 × 10<sup>5</sup> ATX-KO B16-F10 cells. There was no statistical difference between the two genotypes (unpaired <span class="html-italic">t</span>-test, <span class="html-italic">p</span> = 0.1551). (<b>C</b>) Total LPA species in the plasma of Sftpc-WT (white bar, <span class="html-italic">n</span> = 16) and Sftpc-KO (gray bar, <span class="html-italic">n</span> = 23) analyzed by mass spectrometry. Values are mean ± SD. Unpaired <span class="html-italic">t</span>-test, * <span class="html-italic">p</span> = 0.0426. (<b>D</b>) LPA species in the plasma of Sftpc-WT (white bar, <span class="html-italic">n</span> = 16) and Sftpc-KO (gray bar, <span class="html-italic">n</span> = 23) mice analyzed by mass spectrometry. Values are mean ± SD. * <span class="html-italic">p</span> = 0.0305, unpaired <span class="html-italic">t</span>-test. (<b>E</b>) Metastatic nodules in the lungs of Sftpc-WT (white bar, <span class="html-italic">n</span> = 13) and Sftpc-KO (gray bar, <span class="html-italic">n</span> = 10) mice inoculated with 1.5 × 10<sup>5</sup> WT B16-F10 cells. There was no statistical difference between the two genotypes (unpaired <span class="html-italic">t</span>-test, <span class="html-italic">p</span> = 0.1063). (<b>F</b>) ATX activity in the BALF from Sftpc-WT (white bar, <span class="html-italic">n</span> = 13) and Sftpc-KO (gray bar, <span class="html-italic">n</span> = 10) mice. There was no statistical difference between the two genotypes (unpaired <span class="html-italic">t</span>-test, <span class="html-italic">p</span> = 0.052).</p> "> Figure 4
<p>ATX derived from ATII cells does not impact the transmigration ability of B16-F10 cells. (<b>A</b>) Transmigration of WT (white bar) and ATX-KO (gray bar) B16-F10 cells after incubation in complete medium for 6 h. The experiment was performed in quadruplicate wells. No statistical difference was observed (Mann–Whitney, <span class="html-italic">p</span> = 0.083). (<b>B</b>) Transmigration of WT (white bar) and ATX-KO (gray bar) B16-F10 cells in the presence of ATII cells isolated from Sftpc-WT mice plated in the lower chamber. Membranes were analyzed after 6 h of incubation and performed in quadruplicate. No statistical difference was observed (Mann–Whitney, <span class="html-italic">p</span> = 0.404). (<b>C</b>) Transmigration of WT (white bar) and ATX-KO (gray bar) B16-F10 cells in the presence of ATII cells isolated from Sftpc-KO mice plated in the lower chamber. Membranes were analyzed after 6 h of incubation and performed in quadruplicate. No statistical difference was found (Mann–Whitney, <span class="html-italic">p</span> = 0.083).</p> "> Figure 5
<p>Plasma cytokine measurements in naïve Sftpc-WT and Sftpc-KO mice treated with TAM. Flow cytometry was performed to compare the basal concentration levels of 13 cytokines in the plasma of 7 Sftpc-WT (white bars) and 6 Sftpc-KO (gray bars) mice. Note that only IL-27 was different between the groups with a 3-fold higher concentration in the plasma of Sftpc-KO mice (unpaired <span class="html-italic">t</span>-test, * <span class="html-italic">p</span> = 0.032).</p> "> Figure 6
<p>Cytokine measurements in the plasma of Sftpc-WT and Sftpc-KO mice on post-inoculation day 21. Flow cytometry was performed to compare the concentration of 13 cytokines in the plasma of Sftpc-WT (white bars) and Sftpc-KO (gray bars) mice, on day 21 post-inoculation, inoculated with 1.5 × 10<sup>5</sup> ATX-KO B16-F10 cells. Sftpc-KO mice presented an increase in 2 out of the 13 cytokines (unpaired <span class="html-italic">t</span>-test, IFNγ, **** <span class="html-italic">p</span> < 0.0001; TNFα, *** <span class="html-italic">p</span> = 0.0003).</p> "> Figure 7
<p>Immunostaining performed on Sftpc-WT and Sftpc-KO lung sections. Five-micrometer lung sections were stained for (<b>A</b>) CD8a, Sftpc-KO mice presented a higher CD8+ T cell infiltration (black arrows); (<b>B</b>) CD4, both groups presented nodules with sparse CD4+ infiltration; and (<b>C</b>) CD68, no infiltration of CD68<sup>+</sup> cells was observed. Scale bars represent 200 μm (10× magnification).</p> ">
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. CRISPR-Cas9-Edited B16-F10 Cells and Isolation of Murine ATII Cells
2.2. Animal Models
2.3. Tamoxifen Treatment
2.4. Measurement of ATX Activity
2.5. Western Blotting
2.6. Histology and Immunostaining
2.7. Immunofluorescence
2.8. Mass Spectrometry
2.9. Transwell Cell Migration Assay
2.10. Cell Proliferation Assay
2.11. Cytokine Measurement
2.12. Statistical Analysis
3. Results
3.1. Generation and Validation of an Inducible Conditional KO Mice in Which ATX Is Specifically Deleted in ATII Cells
3.2. Generation and Characterization of ATX-KO B16-F10 Cell Line
3.3. Deleting ATX from ATII Cells Reduces the Number of ATX-KO B16-F10 Lung Metastases
3.4. Changes in Immunological Response Associated with Deleting ATX in ATII Cells
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Dacheux, M.A.; Lee, S.C.; Shin, Y.; Norman, D.D.; Lin, K.-H.; E, S.; Yue, J.; Benyó, Z.; Tigyi, G.J. Prometastatic Effect of ATX Derived from Alveolar Type II Pneumocytes and B16-F10 Melanoma Cells. Cancers 2022, 14, 1586. https://doi.org/10.3390/cancers14061586
Dacheux MA, Lee SC, Shin Y, Norman DD, Lin K-H, E S, Yue J, Benyó Z, Tigyi GJ. Prometastatic Effect of ATX Derived from Alveolar Type II Pneumocytes and B16-F10 Melanoma Cells. Cancers. 2022; 14(6):1586. https://doi.org/10.3390/cancers14061586
Chicago/Turabian StyleDacheux, Mélanie A., Sue Chin Lee, Yoojin Shin, Derek D. Norman, Kuan-Hung Lin, Shuyu E, Junming Yue, Zoltán Benyó, and Gábor J. Tigyi. 2022. "Prometastatic Effect of ATX Derived from Alveolar Type II Pneumocytes and B16-F10 Melanoma Cells" Cancers 14, no. 6: 1586. https://doi.org/10.3390/cancers14061586
APA StyleDacheux, M. A., Lee, S. C., Shin, Y., Norman, D. D., Lin, K.-H., E, S., Yue, J., Benyó, Z., & Tigyi, G. J. (2022). Prometastatic Effect of ATX Derived from Alveolar Type II Pneumocytes and B16-F10 Melanoma Cells. Cancers, 14(6), 1586. https://doi.org/10.3390/cancers14061586