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Tissue-resident glial cells associate with tumoral vasculature and promote cancer progression

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Abstract

Cancer cells are embedded within the tissue and interact dynamically with its components during cancer progression. Understanding the contribution of cellular components within the tumor microenvironment is crucial for the success of therapeutic applications. Here, we reveal the presence of perivascular GFAP+/Plp1+ cells within the tumor microenvironment. Using in vivo inducible Cre/loxP mediated systems, we demonstrated that these cells derive from tissue-resident Schwann cells. Genetic ablation of endogenous Schwann cells slowed down tumor growth and angiogenesis. Schwann cell-specific depletion also induced a boost in the immune surveillance by increasing tumor-infiltrating anti-tumor lymphocytes, while reducing immune-suppressor cells. In humans, a retrospective in silico analysis of tumor biopsies revealed that increased expression of Schwann cell-related genes within melanoma was associated with improved survival. Collectively, our study suggests that Schwann cells regulate tumor progression, indicating that manipulation of Schwann cells may provide a valuable tool to improve cancer patients’ outcomes.

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Data availability

Data will be made available on reasonable request.

Abbreviations

BP:

Biological processes

BV:

Blood vessel

CAFs:

Cancer-associated fibroblasts

CD:

Cluster differentiation

CEUA:

Ethics Animal Care and Use Committee

CTLA-4:

Cytotoxic T lymphocyte Antigen-4

DC:

Dendritic cells

DEGs:

Differentially expressed genes

DMEM:

Dulbecco's modified eagle medium

DT:

Diphtheria toxin

ES:

Effect size

FBS:

Fetal bovine serum

FSC-A:

Forward scatter area

FSC-H:

Forward scatter height

GFAP:

Glial fibrillary acidic protein

GFP:

Green fluorescent protein

GO:

Gene ontology

iDTR:

Diphtheria toxin receptor

IFN-γ:

Interferon gamma

IL:

Interleukin

NGFR:

Nerve growth factor receptor

NG2:

Neuron-glial antigen 2

NK:

Natural killer

OCT:

Tissue-Tek

p75:

Neurotrophin-75

PBS:

Phosphate-buffered saline

PD-1:

Programmed cell death protein 1

PDGFRβ:

Platelet-derived growth factor receptor beta

PFA:

Paraformaldehyde

Plp1:

Proteolipid protein 1

SC:

Schwann cell

SKCM:

Skin cutaneous melanoma

TCGA:

The cancer genome atlas

TH:

Tyrosine hydroxylase

TNBC:

Triple-negative breast cancer

TUBB3:

Class III β tubulin

UFMG:

Federal University of Minas Gerais

UMAP:

Uniform Manifold Approximation and Projection

WT:

Wild-type

γδ:

Gamma Delta

SEM:

Standard error

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Acknowledgements

Alexander Birbrair is supported by a research productivity fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-PQ2), a grant from Instituto Serrapilheira/Serra-1708-15285, a Grant from Pró-reitoria de Pesquisa/Universidade Federal de Minas Gerais (PRPq/UFMG) (Edital 05/2016); a grant from Fundação de Amparo à Pesquisa do Estado de Minas Gerais—FAPEMIG (Chamada N°01/2021—Demanda Universal, APQ-01321-21); a grant from FAPEMIG [Rede Mineira de Pesquisa Translacional em Imunobiológicos e Biofármacos no Câncer (REMITRIBIC, RED-00031-21)]; a grant from FAPEMIG [Rede Mineira de Engenharia de Tecidos e Terapia Celular (REMETTEC, RED-00570-16)]; a grant from FAPEMIG [Rede De Pesquisa Em Doenças Infecciosas Humanas E Animais Do Estado De Minas Gerais (RED-00313-16)]; and a grant from MCTIC/CNPq Nº 28/2018 (Universal/Faixa A). Akiva Mintz is supported by the National Institute of Health (1R01CA179072-01A1) and by the American Cancer Society Mentored Research Scholar grant (124443-MRSG-13-121-01-CDD). Edroaldo Lummertz da Rocha is supported by the Coordination for the Improvement of Higher Education Personnel (CAPES), the National Council of State Funding Agencies (CONFAP), the Serrapilheira Institute and the Foundation for Support of Research and Innovation of Santa Catarina (FAPESC). Marcelo Falchetti is supported by a postdoctoral fellowship from the Brazilian National Council for Scientific and Technological Development (CNPq), Brazil. Remo C. Russo is supported by a research productivity fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq-PQ2) and a Grant from FAPEMIG (Chamada N°01/2021 – Demanda Universal, APQ-02571-21). Pedro A F Galante was supported by a research productivity fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico, a grant from Instituto Serrapilheira, and a grant from São Paulo Research Foundation (FAPESP), grant 2012/24731-1. Gabriela D. A. Guardia was supported by São Paulo Research Foundation (FAPESP), grant 2017/19541-2, and a fellowship from Hospital Sirio-Libanês, Young Scientist initiative. Caroline C. Picoli and Alinne C. Costa are supported by doctoral fellowships from CAPES. Bryan O. P. Gonçalves is supported by a doctoral fellowship from FAPEMIG. Gabryella S.P. Santos is supported by a doctoral fellowship from CNPq. Beatriz G. S. Rocha and Walison N. Silva are supported by master fellowships from CAPES. Milla R. Almeida is supported by a scientific initiation fellowship from CNPq. Pedro A. C. Costa is supported by a postdoctoral fellowship (PNPD) from CAPES. The authors also thank CAPI (UFMG) for microscopical technical support and Laboratory of Flow Cytometry at the Instituto de Ciências Biológicas/UFMG (http://labs.icb.ufmg.br/citometria/)” for providing the equipment and technical support for experiments involving flow cytometry.

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Authors and Affiliations

  1. Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil

    Beatriz G. S. Rocha, Caroline C. Picoli, Bryan O. P. Gonçalves, Walison N. Silva, Alinne C. Costa, Michele M. Moraes, Pedro A. C. Costa, Gabryella S. P. Santos, Milla R. Almeida & Alexander Birbrair

  2. Department of Cell Biology, Ezequiel Dias Foundation, Belo Horizonte, MG, Brazil

    Luciana M. Silva

  3. Hospital Israelita Albert Einstein, São Paulo, SP, Brazil

    Youvika Singh & Helder I. Nakaya

  4. Department of Microbiology and Immunology, Federal University of Santa Catarina, Florianópolis, Brazil

    Marcelo Falchetti & Edroaldo L. Rocha

  5. Centro de Oncologia Molecular, Hospital Sirio-Libanes, Sao Paulo, SP, Brazil

    Gabriela D. A. Guardia & Pedro A. F. Galante

  6. Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil

    Pedro P. G. Guimarães & Remo C. Russo

  7. Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil

    Rodrigo R. Resende

  8. Institute of Biological Sciences, Federal University of Goiás, Goiânia, GO, Brazil

    Mauro C. X. Pinto

  9. Center of Biological Sciences and Health, Federal University of Western Bahia, Barreiras, BA, Brazil

    Jaime H. Amorim

  10. Department of Genetics, Ecology and Evolution, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil

    Vasco A. C. Azevedo

  11. Department of Dermatology, University of Wisconsin-Madison, Medical Sciences Center, Rm 4385, 1300 University Avenue, Madison, WI, 53706, USA

    Alexandre Kanashiro & Alexander Birbrair

  12. Department of Radiology, Columbia University Medical Center, New York, NY, USA

    Akiva Mintz & Alexander Birbrair

  13. Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York, NY, USA

    Paul S. Frenette

  14. Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY, USA

    Paul S. Frenette

  15. Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA

    Paul S. Frenette

Authors
  1. Beatriz G. S. Rocha
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  2. Caroline C. Picoli
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  9. Milla R. Almeida
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  10. Luciana M. Silva
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  11. Youvika Singh
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  12. Marcelo Falchetti
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  22. Edroaldo L. Rocha
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  26. Alexander Birbrair
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Contributions

AB conceived and supervised the study; BGSR, CCP, BOPG, WNS, ACC, MMM, PACC, GSPS, MRA, LMS, YS, MF, GDAG, PPGG, RCR, RRR, MCXP, JHA, VACA, AK, HIN, ELR, PAFG, AB analyzed the data and discussed the results; AB was responsible for funding; AM, PSF, AB wrote the original draft; all authors contributed to and approved the final version of the manuscript.

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Correspondence to Alexander Birbrair.

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Beatriz G. S. Rocha, Caroline C. Picoli and Bryan O. P. Gonçalves are co-first authors.

Supplementary Information

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Supplementary file1 (PDF 371 kb)

Supplementary file2 (PDF 91 kb)

Supplementary file3 (PDF 324 kb)

Supplementary file4 (PDF 973 kb)

Supplementary file5 (PDF 564 kb)

Supplementary file6 (PDF 547 kb)

10456_2022_9858_MOESM7_ESM.tif

Supplementary Figure 1. Nerves infiltrate within the tumor microenvironment. A. Adult wild-type mice were orthotopically injected with Tramp-C2 prostate cancer cells. The tumors were surgically removed 2 weeks later for analysis. B. Percentage of blood vessels with or without Peripherin+ nerve fibers attached to them in the Tramp-C2 prostate cancer microenvironment (n=3 mice) (81.25 ± 4.54 % of blood vessels were not associated to Peripherin+ nerve fibers; p < 0.0001; ES =15.7L). C and D. Representative images of sections from orthotopic Tramp-C2 tumors show nerves within the prostate tumor microenvironment. C. All panels show the same area for different channels: Peripherin (marker of peripheral nerve fibers), CD31 (marker of endothelial cells), DAPI, and all three merged. The area in the white box is magnified showing a nerve fiber attached to a blood vessel within the prostate tumor microenvironment. D. All panels show the same area for different channels: PGP9.5 (neuronal marker), CD31, DAPI, and merged. E. Percentage of blood vessels with or without PGP9.5+ nerve fibers attached to them in the Tramp-C2 prostate cancer microenvironment (n=3 mice) (79.7 ± 6.2 % of blood vessels were not associated to PGP9.5+ nerve fibers; p < 0.0001; ES =9.8L). F, G and H. Sympathetic nerves are present in the prostate tumor microenvironment. F. Intra-prostatic injection of TdTomato-labeled PC-3 human prostate cancer cells in nude mice, and tumor analysis after 3 weeks. G. Representative photomicrographs of a prostate tumor section 3 weeks after PC3 cells injection, showing blood vessels with and without attached TH+ nerve fibers. H. Percentage of blood vessels with or without attached TH+ nerve fibers in the PC3 prostate tumor microenvironment after 3 weeks (n=3 mice) (83.6 ± 4.2 % of blood vessels were not associated to TH+ nerve fibers; p < 0.0001; ES =5.4L). Data are mean ± SEM. TH, tyrosine hydroxylase, sympathetic neuron marker. Statistical analysis: unpaired Student's t-tests. ES: effect size; Llarge (≥ 1.2). ***p <0.001. Scale bars, 50µm (C and D) and 10 µm (G). (TIF 5864 kb)

10456_2022_9858_MOESM8_ESM.tif

Supplementary Figure 2. GFAP+ cells are present in the microenvironment of syngeneic C57BL6 mouse prostate tumors. A. Adult wild-type mice orthotopically injected with Tramp-C2 prostate cancer cells. B. Percentages of GFAP+ cells attached or not to blood vessels in the Tramp-C2 tumor after 2 weeks (n=3 mice) (93.7 ± 2.7 % of GFAP+ cells were associated to blood vessels, while 6.3 ± 2.7 % were not associated to blood vessels; p < 0.0001; ES =21.75L). C. Prostate Tramp-C2 tumor surgically removed after 2 weeks. D. Representative image of a section from orthotopic Tramp-C2 tumor shows blood vessel-associated GFAP+ cells in C57BL/6 mice. All panels show the same area for different channels (GFAP, CD31, and the two images merged with DAPI). E, F and G. GFAP+ cells are present within RM1 prostate tumor microenvironment associated with blood vessels. E. Intra-prostatic injection of RM1 prostate cancer cell line (from Ras+Myc transformed mouse prostate carcinoma) in wild-type mice, and tumor analysis after 2 weeks. F. Percentages of GFAP+ cells attached or not to blood vessels in the RM1 tumor after 2 weeks (n=3 mice) (91.0 ± 5.7 % of GFAP+ cells were associated to blood vessels, while 9.0 ± 5.6 % were not associated to blood vessels; p < 0.0001; ES =9.11L). G. Representative photomicrographs of a prostate tumor section 2 weeks after RM1 cells injection, showing blood vessels with GFAP+ cells attached to it. Statistical analysis: unpaired Student's t-tests. ES: effect size; Llarge (≥ 1.2). ***p <0.001. Data are mean ± SEM. Scale bars, 10µm. (TIF 3503 kb)

10456_2022_9858_MOESM9_ESM.tif

Supplementary Figure 3. Tumor-infiltrating perivascular glial cells differ from pericytes. A. Representative photomicrographs of prostate tumor sections 2 weeks after Tramp-C2 cells orthotopic injection into Nestin-GFP/NG2-DsRed mice showing GFAP+ cells (blue). B. Percentage of NG2-DsRed+ cells expressing GFAP in the Tramp-C2 prostate tumor after 2 weeks (n=5 mice) (23.60 ± 4.69 % of NG2-DsRed+ cells were positive for GFAP; p < 0.001; ES = 5.3L). C. Representative photomicrographs of melanoma tumor sections 2 weeks after B16F10 cancer cells transplantation into Plp1-CreER/TdTom mice showing perivascular Plp1CreER+/TdTomato+ cells (red) not expressing PDGFRβ (green). D. Percentage of Plp1CreER+/TdTomato+ cells not expressing PDGFRβ in the B16F10 tumor after 2 weeks (n=5 mice) (99.9 ± 0.10 % of Plp1CreER+/TdTomato+ cells were negative for PDGFRβ; p < 0.001; ES = 998.0L). Statistical analysis: unpaired Student's t-tests. ES: effect size; Llarge (≥ 1.2). ***p <0.001. Data are mean ± SEM. Scale bars, 10µm. (TIF 3434 kb)

10456_2022_9858_MOESM10_ESM.tif

Supplementary Figure 4. Ablation of Schwann cells increases the number of tumor-infiltrating dendritic cells. Dendritic cells from B16F10–inoculated mice were analyzed ex vivo in Plp1-CreER-/iDTR+ (n = 6 mice) and Plp1-CreER+/iDTR+ (n = 9 mice) mice. A. Absolute number of dendritic cells from the melanomas of B16F10–inoculated mice (Plp1-CreER-/iDTR+: 2.72x106 ± 7.40x105 cells per mg of tumor; Plp1-CreER+/iDTR+: 8.60x106 ± 2.21x106 cells per mg of tumor; p=0.039; ES = 1.2L). B. Absolute number of HLA-DR+ dendritic cells dendritic cells from the melanomas of B16F10–inoculated mice (Plp1-CreER-/iDTR+: 2.27x107 ± 2.87x106 cells per mg of tumor; Plp1-CreER+/iDTR+: 5.01x107± 9.40x106 cells per mg of tumor; p = 0.029; ES = 1.3L). Statistical analysis: unpaired Student's t-tests one-tailed. ES: effect size; Llarge (≥ 1.2). Plp1-CreER-/iDTR+ (n = 6 mice) and Plp1-CreER+/iDTR+ (n = 9 mice). * p <0.05. Data are mean ± SEM. (TIF 526 kb)

10456_2022_9858_MOESM11_ESM.tif

Supplementary Figure 5. Tumor-infiltrating Treg cells are reduced by Schwann cell ablation. Regulatory T cells from B16F10–inoculated mice were analyzed ex vivo in Plp1-CreER-/iDTR+ (n = 6 mice) and Plp1-CreER+/iDTR+ (n = 9 mice) mice. A. Absolute number of Treg cells from the melanomas of B16F10–inoculated mice (Plp1-CreER-/iDTR+: 4.25x106 ± 7.18x105 cells per mg of tumor; Plp1-CreER+/iDTR+: 1.48x106 ± 4.20x105 cells per mg of tumor, p=0.006; ES = 1.8L). Column charts show proportion of CTLA-4 (B), PD-1 (C) and CTLA-4/PD-1 co-expressing (D) Treg cells from tumors of B16F10–inoculated mice. B. CTLA-4+ Regulatory T cells (Plp1-CreER-/iDTR+: 14.35 ± 1.95%; Plp1-CreER+/iDTR+: 17.06 ± 2.03%; p = 0.363; ES = 0.5S). C. PD-1+ Regulatory T cells (Plp1-CreER-/iDTR+: 19.10 ± 3.72%; Plp1-CreER+/iDTR+: 9.24 ± 3.31%; p = 0.036; ES = 1.1M). D. and CTLA-4+/PD-1+ Regulatory T cells (Plp1-CreER-/iDTR+: 4.01 ± 0.88%; Plp1-CreER+/iDTR+: 2.67 ± 0.70%; p = 0.1305; ES = 0.7M). Statistical analysis: unpaired Student's t-tests or Mann-Whitney Rank Sum Test one-tail. ES: effect size; Ttrivial (< 0.2); Ssmall (0.2–0.6); Mmedium (0.6–1.2); Llarge (≥ 1.2). *p<0.05 and **p<0.01. Data are mean ± SEM. (TIF 553 kb)

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Rocha, B.G.S., Picoli, C.C., Gonçalves, B.O.P. et al. Tissue-resident glial cells associate with tumoral vasculature and promote cancer progression. Angiogenesis 26, 129–166 (2023). https://doi.org/10.1007/s10456-022-09858-1

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