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PreprintCited by 12Caveolin-1 and cellular processesMechanisms of cancer metastasisCancer Cells and Metastasis

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Caveolin-1 Knockout Mitigates Breast Cancer Metastasis to the Lungs via Integrin α3 Dysregulation.

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Francis, Joseph, Singh, Dhirendra, Pathak, Rashmi, Pandit, Abhishek, Ebenezer, Philip, Kumar, Sanjay, Duplooy, Alexander, White, Mary, Jambunathan, Nithya, Chintalaramulu, Naveen, Dharmakumar, Rohan·2023·Cancer Gene Therapy
DOI 10.21203/rs.3.rs-3677189/v1PMC PMC11567888

Preprint — published as 10.1038/s41417-024-00821-4 · Paper page

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Abstract

Caveolin-1 (Cav-1) is a critical lipid raft protein playing divergent roles as both a tumor suppressor and promoter. While its role in tumorigenesis, progression, and metastasis is recognized, explicit contribution of Cav-1 to the onset of lung metastasis from primary breast malignancies remained vague. We exhibit here, the first-ever evidence of Cav-1 knockout in epithelial cells leading to a significant reduction in lung metastasis in syngeneic mouse models of breast cancer. In vitro, Cav-1 knockout in 4T1 cells suppressed extracellular vesicles secretion, cellular motility, and MMP secretion vis-à-vis the controls. Complementing this, our in vivo analyses demonstrated a marked reduction in lung metastatic foci in mice injected with Cav-1 knockout 4T1 cells as compared to wild-type mice, which was further corroborated by mRNA profiling of the primary tumor. We discerned 21 epithelial cell migration genes exhibiting varied expression in tumors derived from Cav-1 knockout versus wild-type 4T1 cells. Correlation analysis and immunoblotting further divulged that Cav-1 regulates metastasis via integrin α3 (ITGα3). In silico protein docking anticipated an interaction between Cav-1 and ITGα3, substantiated by co-immunoprecipitation. Furthermore, ITGα3 knockdown corroborated its role in metastasis in a cell migration assay. Therefore, it can be inferred that Cav-1 plays a pivotal role in the pre-metastatic niche establishment and facilitates lung-specific cell migration.

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Fig. 1 Characterization of the effects of Cav-1 deficiency in 4T1 cells. CRISPR/Cas9 was used to target Cav-1 in 4T1 cells. A Immunoblot showing absence of Cav-1 protein expression in purified Cav-1 knockout cells as compared to control 4T1 cells. B MTT assay showing that knocking out Cav-1 did not affect cell viability at 48 h. C Cell cycle assay showing no significant differences in the diverse phases of cell growth using flow cytometry. D The cell mitochondrial stress assay showed no significant effect on mitochondrial respiration in Cav-1 KO mice compared to control 4T1 cells using an Agilent Seahorse XF Analyzer. E SEM Image showing comparative cell surface morphology. F TEM images show altered membrane morphology and vesicle release. G Immunoblot showing reduced expression of exosome markers in the extracellular vesicles isolated from Cav-1 KO cell growth media and control after 24 h. H Densitometry data showing reduced expression of Annexin V and Alix in Cav-1 KO conditioned media compared to WT 4T1 conditioned media. I Wound healing assay showing reduced migration ability of Cav-1 KO cells compared to control 4T1 cells. J MMP fluorometric assay showed significantly reduced secretion of MMPs in Cav-1 KO mice compared to control 4T1 cells in conditioned media. Statistical analysis was performed using unpaired Student’s t-test *P < 0.05; ***P < 0.001.
Fig. 1 Characterization of the effects of Cav-1 deficiency in 4T1 cells. CRISPR/Cas9 was used to target Cav-1 in 4T1 cells. A Immunoblot showing absence of Cav-1 protein expression in purified Cav-1 knockout cells as compared to control 4T1 cells. B MTT assay showing that knocking out Cav-1 did not affect cell viability at 48 h. C Cell cycle assay showing no significant differences in the diverse phases of cell growth using flow cytometry. D The cell mitochondrial stress assay showed no significant effect on mitochondrial respiration in Cav-1 KO mice compared to control 4T1 cells using an Agilent Seahorse XF Analyzer. E SEM Image showing comparative cell surface morphology. F TEM images show altered membrane morphology and vesicle release. G Immunoblot showing reduced expression of exosome markers in the extracellular vesicles isolated from Cav-1 KO cell growth media and control after 24 h. H Densitometry data showing reduced expression of Annexin V and Alix in Cav-1 KO conditioned media compared to WT 4T1 conditioned media. I Wound healing assay showing reduced migration ability of Cav-1 KO cells compared to control 4T1 cells. J MMP fluorometric assay showed significantly reduced secretion of MMPs in Cav-1 KO mice compared to control 4T1 cells in conditioned media. Statistical analysis was performed using unpaired Student’s t-test *P < 0.05; ***P < 0.001.CC BY · PubMed Central
Fig. 2 Cav-1 regulates 4T1 growth and lung metastasis in vivo. 4T1 cells were injected into the mammary pads of BALB/c mice. Tumor progression and lung metastasis were followed for 4 weeks: A Green arrow in the image showing delayed tumor growth in Cav-1 KO injected mice compared to WT 4T1 injected mice at the end of week 1; B comparative tumor area (length × width) at the end of weeks 2 and 3; C Graph showing relative tumor weight at the end of weeks 2 and 3; D Image showing visible metastatic lesions in the WT lungs at the end of week 4, which were not present in the Cav-1 KO cell-injected mice; E H&E staining of lungs, yellow arrows show metastatic foci in WT, but no metastasis was seen in Cav-1 KO cells injected lungs at different time points. Statistical analysis was performed using unpaired Student’s t-test *P < 0.05; ***P < 0.001.
Fig. 2 Cav-1 regulates 4T1 growth and lung metastasis in vivo. 4T1 cells were injected into the mammary pads of BALB/c mice. Tumor progression and lung metastasis were followed for 4 weeks: A Green arrow in the image showing delayed tumor growth in Cav-1 KO injected mice compared to WT 4T1 injected mice at the end of week 1; B comparative tumor area (length × width) at the end of weeks 2 and 3; C Graph showing relative tumor weight at the end of weeks 2 and 3; D Image showing visible metastatic lesions in the WT lungs at the end of week 4, which were not present in the Cav-1 KO cell-injected mice; E H&E staining of lungs, yellow arrows show metastatic foci in WT, but no metastasis was seen in Cav-1 KO cells injected lungs at different time points. Statistical analysis was performed using unpaired Student’s t-test *P < 0.05; ***P < 0.001.CC BY · PubMed Central
Fig. 3 RNA was isolated from each tumor group, and mRNA sequencing analysis was performed. A Heat map showing cluster analysis of differentially expressed genes in Cav-1 KO and WT 4T1 cell-induced tumors; B Volcano plot showing differential gene expression between Cav-1 KO and WT 4T1 cell-induced tumors at weeks 2 and 3. DEG were also plotted between WT with WT and KO with KO between week 2 and 3 (C). DEG (padj < 0.05) were categorized into biological processes (BP), cellular component (CC), and molecular function (MF). DESeq at threshold DESeq2, P-value ≤ 0.05.
Fig. 3 RNA was isolated from each tumor group, and mRNA sequencing analysis was performed. A Heat map showing cluster analysis of differentially expressed genes in Cav-1 KO and WT 4T1 cell-induced tumors; B Volcano plot showing differential gene expression between Cav-1 KO and WT 4T1 cell-induced tumors at weeks 2 and 3. DEG were also plotted between WT with WT and KO with KO between week 2 and 3 (C). DEG (padj < 0.05) were categorized into biological processes (BP), cellular component (CC), and molecular function (MF). DESeq at threshold DESeq2, P-value ≤ 0.05.CC BY · PubMed Central
Fig. 4 Knocking out Cav-1 affects gene expression involved in epithelial cell migration. A Heatmap demonstrating that knocking out Cav-1 expression significantly affected 53 genes at week 2 and 49 genes at week 3. B Heatmap showing DEG, which is known to be involved in epithelial cell migration and expressed at specific time points in either week 2 or week 3. DESeq at threshold DESeq2, P-value ≤ 0.05.
Fig. 4 Knocking out Cav-1 affects gene expression involved in epithelial cell migration. A Heatmap demonstrating that knocking out Cav-1 expression significantly affected 53 genes at week 2 and 49 genes at week 3. B Heatmap showing DEG, which is known to be involved in epithelial cell migration and expressed at specific time points in either week 2 or week 3. DESeq at threshold DESeq2, P-value ≤ 0.05.CC BY · PubMed Central
Fig. 5 The deletion of Cav-1 significantly altered the expression of epithelial cell migration genes at weeks 2 and 3. A Heatmap showing a set of epithelial migration genes that might play a regulatory role in Cav-1 KO-hampered lung metastasis at weeks 2 and 3. The Y-axis represents the metastatic genes, whereas the X-axis represents the different groups. B Graphical representation of epithelial migration genes at week 2 and C week 3. Y-axis represents FPKM value, and X-axis represents the gene name. DESeq at threshold DESeq2, P-value ≤ 0.05.
Fig. 5 The deletion of Cav-1 significantly altered the expression of epithelial cell migration genes at weeks 2 and 3. A Heatmap showing a set of epithelial migration genes that might play a regulatory role in Cav-1 KO-hampered lung metastasis at weeks 2 and 3. The Y-axis represents the metastatic genes, whereas the X-axis represents the different groups. B Graphical representation of epithelial migration genes at week 2 and C week 3. Y-axis represents FPKM value, and X-axis represents the gene name. DESeq at threshold DESeq2, P-value ≤ 0.05.CC BY · PubMed Central
Fig. 6 Data mining from the Human Breast Cancer Gene Expression Miner (Breast Cancer Gene-Expression Miner v4.8) database showed that Cav-1 expression was correlated with patient outcome and mortality in TNBC. A Correlation analysis between Cav-1 and 21 significantly differentially expressed genes in the human breast cancer patient database. B Significant correlation between Cav-1 and CDH13, KDR, MMRN2 (n = 317), and PECAM-1 (n = 254) expression in TNBC patients with breast cancer. C Immunoblot showing variable gene expression between Cav-1 KO and WT 4T1 injected tumors, which was more prominent at the end of week 3.
Fig. 6 Data mining from the Human Breast Cancer Gene Expression Miner (Breast Cancer Gene-Expression Miner v4.8) database showed that Cav-1 expression was correlated with patient outcome and mortality in TNBC. A Correlation analysis between Cav-1 and 21 significantly differentially expressed genes in the human breast cancer patient database. B Significant correlation between Cav-1 and CDH13, KDR, MMRN2 (n = 317), and PECAM-1 (n = 254) expression in TNBC patients with breast cancer. C Immunoblot showing variable gene expression between Cav-1 KO and WT 4T1 injected tumors, which was more prominent at the end of week 3.CC BY · PubMed Central
Fig. 7 Cav-1 promotes epithelial cell migration by interacting with ITGα3. A Interaction between Cav-1 and ITGα3, as predicted using the in silico protein interaction ZDOCK server (https://zdock.umassmed.edu/). B Coimmunoprecipitation of Cav-1 and ITGα3 confirmed their physical interactions. C Wound healing assay of Cav-1 and ITGα3 knock down 4T1 cells showed impaired epithelial cell migration after 24 and 48 h of scratch formation. Graph showing wound closure in the different groups at these time points. Statistical analysis was performed using unpaired Student’s t-test *P < 0.05; ***P < 0.001.
Fig. 7 Cav-1 promotes epithelial cell migration by interacting with ITGα3. A Interaction between Cav-1 and ITGα3, as predicted using the in silico protein interaction ZDOCK server (https://zdock.umassmed.edu/). B Coimmunoprecipitation of Cav-1 and ITGα3 confirmed their physical interactions. C Wound healing assay of Cav-1 and ITGα3 knock down 4T1 cells showed impaired epithelial cell migration after 24 and 48 h of scratch formation. Graph showing wound closure in the different groups at these time points. Statistical analysis was performed using unpaired Student’s t-test *P < 0.05; ***P < 0.001.CC BY · PubMed Central

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Metadata

Authors
Francis, J., Singh, D., Pathak, R., Pandit, A., Ebenezer, P., Kumar, S., Duplooy, A., White, M., Jambunathan, N., Chintalaramulu, N., & Dharmakumar, R.
Affiliations
  • Louisiana State University (US)
  • Indiana University School of Medicine (US)
  • Midwestern University (US)
Corresponding author
Francis, Joseph
ORCID
Venue
Cancer Gene Therapy
Publisher
Springer Science and Business Media LLC
Published
2023-12-12
Volume
31
Issue
11
Pages
1658-1668
ISSN
0929-1903 (ISSN-L)
DOI
10.21203/rs.3.rs-3677189/v1
PMC
PMC11567888
OpenAlex
W4402331411
Cited by
12
References
1
Citations by year
2026: 5 · 2025: 5 · 2024: 2
FWCI
2.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Gene Therapy (publishedVersion, cc-by)
  • Research Square (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
Funders
National Institute of General Medical Sciences (P20GM135000)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
caveolin-1, breast cancer lung metastasis, integrin alpha3, 4T1 cells, extracellular vesicles, cell migration, matrix metalloproteinases, lipid rafts
MeSH terms
Animals, Breast Neoplasms, Cell Movement, Disease Models, Animal, Female, Humans, Lung Neoplasms, Mice, Inbred BALB C, Gene Expression Regulation, Neoplastic, Mice, Knockout, Integrin alpha3, Cell Line, Tumor, Caveolin 1, Mice, Gene Knockout Techniques

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