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Severely polarized extracellular acidity around tumour cells

Nature Biomedical Engineering (2024)Cite this article

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Abstract

Extracellular pH impacts many molecular, cellular and physiological processes, and hence is tightly regulated. Yet, in tumours, dysregulated cancer cell metabolism and poor vascular perfusion cause the tumour microenvironment to become acidic. Here by leveraging fluorescent pH nanoprobes with a transistor-like activation profile at a pH of 5.3, we show that, in cancer cells, hydronium ions are excreted into a small extracellular region. Such severely polarized acidity (pH <5.3) is primarily caused by the directional co-export of protons and lactate, as we show for a diverse panel of cancer cell types via the genetic knockout or inhibition of monocarboxylate transporters, and also via nanoprobe activation in multiple tumour models in mice. We also observed that such spot acidification in ex vivo stained snap-frozen human squamous cell carcinoma tissue correlated with the expression of monocarboxylate transporters and with the exclusion of cytotoxic T cells. Severely spatially polarized tumour acidity could be leveraged for cancer diagnosis and therapy.

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Fig. 1: SPEAR of cancer cells revealed by UPS nanoprobes.
Fig. 2: Quantitative analysis of SPEAR in multiple cancer cell lines.
Fig. 3: Glycolysis-mediated lactic acid export drives SPEAR formation.
Fig. 4: Direction control of SPEAR formation.
Fig. 5: Imaging tumour acidosis in human head/neck tumour sample and T cell exclusion.

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Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. The raw imaging files generated during the study are too large to be publicly shared, yet they are available for research purposes from the corresponding author on reasonable request. De-identified patient-related data are available from the corresponding author, subject to approval from the Institutional Review Board of the University of Texas Southwestern Medical Center. Source data are provided with this paper.

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Acknowledgements

We thank J. Shay, J. Minna and T.C. Wu for providing cell lines for this study. We thank Z. Wang, S. Li and P. Shaji for the assistance on polymer synthesis and characterization, and W. Li and T. Vo for the in vivo imaging study and in vitro cell culture assays. The study was supported by the National Institutes of Health grants R01CA211930 (to J.G.) and R01CA13291074 (to B.D.S.), the Cancer Prevention Research Institute of Texas grant RP180343 (to J.G.), and the Mendelson-Young endowment in cancer therapeutics (to J.G.).

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Qiang Feng, Zachary Bennett, Raymundo Pantoja, Gang Huang & Jinming Gao

  2. Department of Pharmacology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Qiang Feng, Anthony Grichuk, Tongyi Huang, Gang Huang & Jinming Gao

  3. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Anthony Grichuk & Jinming Gao

  4. Children’s Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Brandon Faubert & Ralph J. DeBerardinis

  5. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Mingyi Chen

  6. Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Ralph J. DeBerardinis

  7. Department of Otolaryngology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Baran D. Sumer & Jinming Gao

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Contributions

J.G. and Q.F. designed the study. Q.F., T.H., A.G., R.P. and G.H. performed the experiments. B.F. prepared the MCT1 and MCT4 knockout HCC827 cell lines. M.C. performed histology analysis. Q.F., A.G. and Z.B. prepared the manuscript. J.G., B.D.S. and R.J.D. supervised the study. J.G., R.J.D. and B.D.S. edited the manuscript.

Corresponding author

Correspondence to Jinming Gao.

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B.D.S. and J.G. are scientific co-founders and advisors of OncoNano Medicine, Inc. The other authors declare no competing interests.

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Nature Biomedical Engineering thanks Alfredo Quinones-Hinojosa and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Characterization of the pH-dependent transition from micelle to unimer state of UPS nanoprobes and proposed models for imaging pH in Matrigel with UPS nanoprobes.

a, Schematic illustration of the pH threshold-dependent phase transition from micelle to unimer state. b, Hydrodynamic diameter of UPS nanoprobes as a function of environmental pH. c-e, DLS analysis of three UPS nanoprobes in the micelle state (pH 7.4) and unimer state (pH below the transition points). f, Schematic illustration of two biological models for acid secretion and detection using UPS nanoprobes. g, Schematic illustration of pH gradient generated from proton diffusion with or without buffering effect.

Source data

Extended Data Fig. 2 Extracellular acidification rate (ECAR) of HCC827 lung cancer cells and HBEC3-KT cells.

The ECAR analysis was performed with the Agilent Seahorse platform according to the manufacturer’s standard protocol. n = 10-12 biologically independent replicates from one experiment. Assays were repeated for 3 times independently. Data are shown as means ± SEM. P values were determined by two-tail unpaired t-test.

Source data

Extended Data Fig. 3 Distribution of UPS nanoprobe in Matrigel and SPEAR formation by a dual functional always-ON/ON-OFF UPS5.3 nanoprobe.

a, Relative fluorescent intensity as a function of pH for the UPS5.3 with ON-OFF channel (TMR) and always-ON channel (Cy5). b, SPEAR imaging of HCC827 cells with UPS5.3 through ON-OFF channel (TMR) and always-ON channel (Cy5). Data are shown as mean ± s.e.m.

Source data

Extended Data Fig. 4 Cellular photostability of SPEAR detection using UPS5.3-TMR nanoprobe.

a, Representative confocal images of SPEAR after repeated scans. b, Alterations in UPS5.3-TMR signal within SPEAR zones (ON) and background zones (OFF), along with the ON/OFF signal ratio. c, QP and RP analysis of SPEAR from 60 scans show consistent measurement using ratio of ON/OFF signal (n = 4 replicates). Data are shown as mean ± s.e.m.

Source data

Extended Data Fig. 5 Representative cell images from SPEAR imaging.

a, Confocal images of the time course of SPEAR formation with UPS5.3-TMR in HN5 human head/neck cancer cells. b, Confocal images of SPEAR formation from different cancer and normal cell lines with UPS5.3-TMR at physiological glucose condition (5 mM) after 30-min incubation. Confocal images were acquired on a Zeiss laser confocal microscope (LM710 model).

Source data

Extended Data Fig. 6 Extracellular acidification rate (ECAR) and lactate secretion of different cell lines.

a, ECAR of HCC827 cells, HCC827 MCT1 knockout and HCC827 MCT4 knockout cells. The ECAR analysis was performed with the Agilent Seahorse platform according to the manufacturer’s standard protocol. b, Lactate secretion from HCC827 cells measured with a NOVA bioanalyzer. n = 10-12 biologically independent replicates from one experiment (a). Assays were repeated for 3 times independently. n = 6 biologically independent replicates from two independent experiments (b). Data are shown as means ± SEM. P value was determined by one-tail, one-way ANOVA.

Source data

Extended Data Fig. 7 L-Lactate but not D-lactate suppresses SPEAR formation.

a, L-Lactate secretion of HCC827 cells measured with NOVA bioanalyzer (n = 5). b, Confocal images and quantification of SPEAR of HCC827 cells treated with D-Lactate (40 mM) or L-Lactate (40 mM). Scale bar: 10 μm. n = 10 from two independent experiments. c, ECAR of HCC827 cells treated with D-Lactate (20 mM) or L-Lactate (20 mM). P values were determined by one-tail one-way ANOVA. Data are shown as mean ± s.e.m. (a,c).

Source data

Extended Data Fig. 8 In vivo tumor imaging of SPEAR phenotype by UPS5.3 nanoprobe.

a, Treatment regimen for in vivo tumor imaging with UPS5.3. b, Immunohistochemistry staining of MCT1 in HCC827 wild type tumors and HCC827 MCT1 knockout tumors. Scale bar: 10 μm. c, Representative LICOR Pearl images of tumor bearing mice after intravenously injection of UPS5.3. d, Quantification of tumor fluorescence of HCC827 tumors, HCC827 MCT1 knockout tumors and corresponding normal tissues (n = 8). e, Treatment regimen of AZD3965 or lactate, followed by imaging with UPS5.3. f, Quantification of tumor imaging signals of different treatments in HCC827, TC-1 or B16F10 tumor models (n = 4). P values were determined by one-tail one-way ANOVA or t-test. Data are shown as mean ± s.e.m.

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Supplementary information

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Supplementary Video 1

Rotation of a three-dimensional confocal image (Z-stack) of a polarized cap with a pH below 5.3 at 30 min.

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Feng, Q., Bennett, Z., Grichuk, A. et al. Severely polarized extracellular acidity around tumour cells. Nat. Biomed. Eng (2024). https://doi.org/10.1038/s41551-024-01178-7

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