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Glypican-1 identifies cancer exosomes and detects early pancreatic cancer

An Author Correction to this article was published on 05 October 2022

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Abstract

Exosomes are lipid-bilayer-enclosed extracellular vesicles that contain proteins and nucleic acids. They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancer-cell-derived exosomes in the circulation is currently lacking. Using mass spectrometry analyses, we identify a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer-cell-derived exosomes. GPC1+ circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of patients and mice with cancer. GPC1+ crExos were detected in the serum of patients with pancreatic cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreatic disease from patients with early- and late-stage pancreatic cancer. Levels of GPC1+ crExos correlate with tumour burden and the survival of pre- and post-surgical patients. GPC1+ crExos from patients and from mice with spontaneous pancreatic tumours carry specific KRAS mutations, and reliably detect pancreatic intraepithelial lesions in mice despite negative signals by magnetic resonance imaging. GPC1+ crExos may serve as a potential non-invasive diagnostic and screening tool to detect early stages of pancreatic cancer to facilitate possible curative surgical therapy.

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Figure 1: GPC1 is present on cancer exosomes.
Figure 2: GPC1+ crExos are a non-invasive biomarker for pancreatic cancer.
Figure 3: Levels of circulating GPC1+ exosomes inform pancreatic cancer resection outcome.
Figure 4: GPC1+ circulating exosomes predict pancreatic cancer in GEMMs.

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Acknowledgements

Work supported by the Cancer Prevention and Research Institute of Texas and UT MD Anderson Cancer Center. R.K. is also supported by National Institutes of Health (NIH) grants CA-155370, CA-151925, DK 081576 and Metastasis Research Center at the MD Anderson Cancer Center (P30CA016672). V.S.L. is supported by the NIH/NCI under the award number P30CA016672 and the UT MDACC Khalifa Bin Zayed Al Nahya Foundation. D.P.-W. and S.T.G. are supported by the NIH P50-CA094056. Institutional Core Grant CA16672 for High Resolution Electron Microscopy Facility. The Flow Cytometry MDACC core facility is partially funded by NIH P30CA16672. The MDACC Small Animal Imaging Facility is partially funded by NIH grants P30-CA016672 and 5U24-CA126577. S.A.M. is a Human Frontiers Science Program Fellow. C.K. is funded by a Research Fellowship of the Deutsche Forschungsgemeinschaf (DFG). We thank P. A. Kurywchak and S. Kamerkar for the help with the sucrose gradients and K. Dunner Jr for the help with the transmission electron microscopy.

Author information

Authors and Affiliations

Authors

Contributions

S.A.M. conceptually designed and carried out most of the experiments, generated the data and the figures, and wrote the manuscript; L.B.L. carried out most of the experiments; C.K. performed sequencing of primary tumours, performed most of the statistical analysis of the manuscript and supported manuscript writing; A.F.F. optimized, performed and analysed the UPLC–MS data; S.T.G. performed mouse MRI and analysed the data; J.K. performed the GEMM breeding, bleeding, euthanasia and material collection; V.S.L. performed the GEMM breeding, bleeding, euthanasia, material collection and supported manuscript editing; E.A.M. provided breast cancer patient samples and patient history; J.W., N.R., C.R. and C.P. collected and provided serum samples and patient history for analysis; M.F.F. optimized, performed and analyzed the UPLC–MS data; D.P.-W. performed the mouse MRI interpretation and provided support in data interpretation and analysis; R.K. conceived the idea, conceptually designed the study, supervised the project and wrote the manuscript.

Corresponding author

Correspondence to Raghu Kalluri.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Exosome isolation.

a, Exosome concentration and size distribution by NanoSight analysis of culture supernatant from NIH/3T3, MCF10A, HDF, MDA-MB-231 and E10 cells. Size mode: 105 nm (3 technical replicates). b, TEM micrograph of MDA-MB-231-derived exosomes. Top right image shows a digitally zoomed inset. c, TEM micrograph of MDA-MB-231-derived exosomes following immunogold labelling for CD9. Gold particles are depicted as black dots. Top right image shows a digitally zoomed inset. d, Immunoblot of flotillin1 and CD81 in exosomal proteins extracted from culture supernatant of E10, NIH/3T3, MDA-MB-231, MCF10A and HDF cells. e, qRT–PCR measurement of GPC1 mRNA levels in HMEL, HDF, HMLE, MCF7, MDA-MB-231, T3M4, Panc-1 and MIA Paca2 cells. Results are mean ± s.d.; n = 3, 3 biological replicates, with 3 technical replicates each. f, Immunoblot of GPC1 in HMEL, HDF, HMLE, MCF7, MDA-MB-231, T3M4, Panc-1 and MIA Paca2 cell lysates (top). β-actin was used as a loading control (bottom). g, Immunoblot of GPC1 in exosomal protein lysates derived from the culture supernatant of 3 non-tumorigenic cell lines (HDF, HMEL and HMLE) and 5 tumorigenic cell lines (MCF7, MDA-MB-231, T3M4, Panc-1 and MIA Paca2) (top). Flotillin1 was used as loading control (bottom). h, Immunoblot of flotillin1 in exosomal protein lysates from the culture supernatant of MDA-MB-231 and T3M4 following sucrose gradient purification. The protein content is assayed in each of the density layers listed.

Extended Data Figure 2 GPC1+ crExos are derived from cancer cells in tumour-bearing mice.

a, Longitudinal blood collection; nude mice with orthotopic MDA-MB-231 tumours (n = 4 mice). b, Percentage of beads with GPC1+ crExos plotted against average tumour volume (n = 4 mice, each sample analysed in technical triplicates for GPC1). ANOVA, post-hoc Tamhane T2, **P < 0.01, ***P < 0.001. Data are mean ± s.d. c, Correlation between tumour volume and the percentage of beads with GPC1+ crExos (Pearson correlation test). d, NanoSight of exosomes from MDA-MB-231-CD63–GFP cells. Black: all exosomes; green: CD63–GFP+ exosomes (n = 3 technical replicates). e, NanoSight of crExos from mice with a MDA-MB-231-CD63–GFP orthotopic tumour. Black: all exosomes; green: CD63–GFP+ exosomes (n = 3 technical replicates). f, FACS analysis of beads with exosomes from cultured MDA-MB-231 (top left) and MDA-MB-231-CD63–GFP (top middle) cells, and crExos of mice with MDA-MB-231-CD63–GFP orthotopic tumours (bottom left). Staining of CD63–GFP+ (cancer-cell-derived) and CD63–GFP (host-derived) crExos for GPC1 (allophycocyanin (APC)+ bottom right; n = 3 biological replicates and 3 technical replicates). The percentage of positive beads is listed. Negative control: secondary antibody alone (top right).

Extended Data Figure 3 NanoSight analysis in human serum samples.

a, TEM micrograph of serum-derived exosomes from a cancer patient. Top right image shows a digitally zoomed inset. b, TEM micrograph of serum-derived exosomes from a cancer patient after immunogold labelling for CD9. Gold particles are depicted as black dots. Top right image shows a digitally zoomed inset. c, Immunoblot of flotillin1 of exosomal protein lysates from serum of cancer patient following exosome purification by a sucrose gradient. The protein content is assayed in each of the density layers listed. d, Exosome concentration by NanoSight analysis showing the number of exosomes per millilitre of serum derived from healthy donors (n = 100), breast cancer patients (n = 32) and patients with PDAC (n = 190) (ANOVA, post-hoc Tamhane T2, *P < 0.05, ****P < 0.0001; 3 technical replicates). e, Exosomes size distribution by NanoSight analysis showing the mode size of exosomes in 1 ml of serum derived from healthy donors (n = 100), breast cancer patients (n = 32) and patients with PDAC (n = 190) (ANOVA, post-hoc Tukey–Kramer test, ***P < 0.001; 3 technical replicates). f, Scatter dot plots depicting the percentage of beads with GPC1+-bound exosomes purified from the serum of breast cancer patients. The patients are subdivided into three subtypes: luminal A, luminal B and triple-negative breast cancer. g, Scatter plots depicting the serum CA19-9 concentration (U ml−1), evaluated by ELISA, in healthy donors (n = 100), patients with BPD (n = 26), PCPL (n = 5) and PDAC (n = 190). Discovery cohort, ANOVA, post-hoc Tamhane T2, *P < 0.05; ****P < 0.0001; 3 technical replicates. Data are mean ± s.d.

Extended Data Figure 4 Tumour-stage-specific analysis.

a, Table associated with ROC curve analysis depicted in Fig. 1f. bf, ROC curve analysis for the percentage of GPC1+ crExos (red line), CA19-9 serum levels (blue scattered line), exosome concentration (black line) and exosome size (scattered black line) in patients with carcinoma in situ (CIS) or stage I pancreatic cancer (n = 5) (a), stage IIa pancreatic cancer (n = 18) (b), stage IIb pancreatic cancer (n = 117) (c), stage III pancreatic cancer (n = 11) (d), and stage IV pancreatic cancer (n = 41) (e), compared to healthy donors (n = 100) and patients with a benign pancreatic disease (n = 26), total n = 126. g, Table associated with ROC curve analysis depicted in Fig. 1h. CI, confidence interval.

Extended Data Figure 5 Longitudinal human study.

a, Scatter plots of the percentage of beads with GPC1+ crExos by flow cytometry in patients with pancreatic cancer. Patients are divided based on metastatic disease (non-metastatic lesions, lymph node metastases and distant metastases) (ANOVA, post-hoc Tukey–Kramer test, *P < 0.05; 3 technical replicates). b, Scatter plots depicting serum CA19-9 levels (U ml−1) in patients with BPD (n = 4), PCPL (n = 4) and PDAC (n = 29) on the pre-operative day and post-operative day 7 in patients (paired two-tailed Student’s t-test, **P < 0.01; 3 technical replicates). c, d, Multivariate analysis (Cox proportional hazards regression model) of prognostic parameters for overall (c) and disease-specific (d) survival of patients with pancreatic cancer in the longitudinal cohort (n = 29). e, Scatter plots depicting serum GPC1 (ng ml−1) levels by ELISA in patients with BPD (n = 6), PDAC (n = 56) and healthy controls (n = 20) (ANOVA, post-hoc Tukey–Kramer test, **** P < 0.0001; 3 technical replicates). f, ROC curve for circulating GPC1 protein (red line) in patients with pancreatic cancer (n = 56) versus healthy donors (n = 20) and patients with a benign pancreatic disease (n = 26), total n = 6.

Extended Data Figure 6 PDAC GEMM longitudinal study.

a, Schematic diagram depicting the spontaneous development and progression of pancreatic cancer in PKT mice, and haematoxylin and eosin of the pancreas at the indicated time points showing healthy pancreas, and PanIN and PDAC lesions. Scale bars, 100 μm. b, c, Exosome size (b) and concentration (c) assayed by NanoSight analysis from the serum of PKT mice (E: experimental, red) and control mice (C: control, blue) at 4, 5, 6, 7 and 8 weeks of age (ANOVA, post-hoc Tukey–Kramer test, *P < 0.05; 3 technical replicates). d, Graph depicting the time-wise progression of tumour volume measured by MRI and the percentage of GPC1+-bound crExo beads in individual PKT mice (blue: tumour volume, red: percentage of GPC1+ crExos). e, Percentage of GPC1+ crExo beads from control mice (n = 3) and mice with cerulein-induced acute pancreatitis (n = 4) (two-tailed Student’s t-test, ns: not significant; 3 technical replicates). f, Results from ROC curves for the percentage of GPC1+-bound crExo beads, exosome concentration and size in 4-, 5-, 6- and 7-week-old PKT mice (n = 7) versus control (including age-matched littermate healthy control (n = 6) and mice with induced acute pancreatitis (n = 4), n = 10)). Data are mean ± s.d.

Extended Data Figure 7 PDAC GEMM cross-sectional studies.

a, Representative micrographs of haematoxylin-and-eosin-stained pancreas from 16-day-old control mice (left) and PKT mice presenting with (right, encircled) and without (middle) PanIN lesions. Scale bars, 100 μm. b, C t values following qPCR analyses for oncogenic KRAS G12D, wild-type KRAS and 18S internal control RNA from exosomes of 44–48-day-old PKT mice serum segregated using FACS for GPC1+-bead-bound exosomes (red) and GPC1-bead-bound exosomes (blue). Data are mean ± s.d.

Extended Data Figure 8 Raw scatter dot plot depicting flow cytometry analyses of beads with GPC1+-bound exosomes

a, Scatter plots and histogram of flow cytometry analyses of serum exosomes on beads of a representative healthy control (left panels are secondary antibody only; right panels are GPC1 antibody and secondary antibody). b, Scatter plots and histogram of flow cytometry analysis of serum exosomes on beads of a representative pancreatic cancer sample (left panels are secondary antibody only; right panels are with GPC1 antibody and secondary antibody).

Extended Data Table 1 The 48 proteins exclusive to MDA-MB-231 exosomes and histopathological findings and scoring in PKT mice in the cross-sectional study
Extended Data Table 2 Demographics of patients and healthy participants and histological report of patients with chronic pancreatitis

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Supplementary information

Supplementary Figure 1

This file shows the uncropped blots for Extended Data Figures 1d, 1f,1g,1h and 2c. (PDF 77 kb)

Supplementary Table 1

This file contains the protein accession numbers of proteins found In exosomes by UPLC‐MS. (XLS 219 kb)

Supplementary Table 2

This table shows the chromatographic separation and mass spectrometric detection conditions. (PDF 236 kb)

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Melo, S., Luecke, L., Kahlert, C. et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523, 177–182 (2015). https://doi.org/10.1038/nature14581

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