Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth

Maojin Yao; P. Britten Ventura; Ying Jiang; Fausto J. Rodriguez; Lixin Wang; Justin S.A. Perry; Yibo Yang; Kelsey Wahl; Rowena B. Crittenden; Mariko L. Bennett; Lin Qi; Cong Cong Gong; Xiao Nan Li; Ben A. Barres; Timothy P. Bender; Kodi S. Ravichandran; Kevin A. Janes; Charles G. Eberhart; Hui Zong

doi:10.1016/j.cell.2019.12.024

Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth

Maojin Yao, P. Britten Ventura, Ying Jiang, Fausto J. Rodriguez, Lixin Wang, Justin S.A. Perry, Yibo Yang, Kelsey Wahl, Rowena B. Crittenden, Mariko L. Bennett, Lin Qi, Cong Cong Gong, Xiao Nan Li, Ben A. Barres, Timothy P. Bender, Kodi S. Ravichandran, Kevin A. Janes, Charles G. Eberhart, Hui Zong^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

95 Scopus citations

Abstract

The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression. Tumors shape a microenvironmental network by acting as a source of tumor-associated astrocytes that provide paracrine stimulation to microglia to secret IGF1, which is critical for tumor progression in SHH-activated mouse medulloblastoma models.

Original language	English (US)
Pages (from-to)	502-520.e19
Journal	Cell
Volume	180
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2019.12.024
State	Published - Feb 6 2020

Funding

We thank Tajie H. Harris, Chris Doe, David Rowitch, Praveen Raju, Melanie Rutkowski, and Jonathan Kipnis for critical discussions and insightful feedback; Ryan A. Llewellyn, Noel C. Derecki, James C. Cronk, and the UVa Flow Cytometry Core Facility for help with flow analysis; Fujun Qin for helping with GSEA; the UVa Advanced Microscopy Facility for imaging analysis; and Steffen Jung for providing the CX3CR1-CreER mouse line. This project was partially supported by grants DoD W81XWH-11-1-0557 and NIH R01NS097271 to H.Z., R01CA194470 and U01CA215794 to K.A.J., R21HL143025 to T.P.B., and R01NS055089 to C.G.E. P.B.V. was supported by NIH/NINDS pre-doctoral fellowship F31-NS076313 . J.S.A.P. is supported by a Mark Foundation fellowship from the Cancer Research Institute , NCI 1K99CA237728-01 , and the Burroughs Wellcome PDEP award. H.Z. and K.A.J. were Pew Scholars in Biomedical Sciences supported by the Pew Charitable Trusts . We thank Tajie H. Harris, Chris Doe, David Rowitch, Praveen Raju, Melanie Rutkowski, and Jonathan Kipnis for critical discussions and insightful feedback; Ryan A. Llewellyn, Noel C. Derecki, James C. Cronk, and the UVa Flow Cytometry Core Facility for help with flow analysis; Fujun Qin for helping with GSEA; the UVa Advanced Microscopy Facility for imaging analysis; and Steffen Jung for providing the CX3CR1-CreER mouse line. This project was partially supported by grants DoD W81XWH-11-1-0557 and NIH R01NS097271 to H.Z. R01CA194470 and U01CA215794 to K.A.J. R21HL143025 to T.P.B. and R01NS055089 to C.G.E. P.B.V. was supported by NIH/NINDS pre-doctoral fellowship F31-NS076313. J.S.A.P. is supported by a Mark Foundation fellowship from the Cancer Research Institute, NCI 1K99CA237728-01, and the Burroughs Wellcome PDEP award. H.Z. and K.A.J. were Pew Scholars in Biomedical Sciences supported by the Pew Charitable Trusts. This work was designed by M.Y. P.B.V. Y.J. and H.Z. The main experiments were performed by M.Y. P.B.V. and Y.J. with assistance from Y.Y. and K.W. Human tumor materials and data were provided by F.J.R. C.G.E. L.Q. and X.-N.L. The laser capture microdissection experiment was performed by L.W. and M.Y. The sequencing analysis was performed by J.S.A.P. K.S.R. K.A.J. and C.C.G. The flow analysis was performed by R.B.C. and T.P.B. Microglia-specific antibodies were provided by M.L.B. and B.A.B. prior to publication. This manuscript was written by P.B.V. M.Y. Y.J. and H.Z. with input from all co-authors. The authors declare no competing interests.

Keywords

TME
astrocytes
brain tumor
cellular network
medulloblastoma
microglia
paracrine signaling
trans-differentiation
tumor microenvironment

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2019.12.024

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Yao, M., Ventura, P. B., Jiang, Y., Rodriguez, F. J., Wang, L., Perry, J. S. A., Yang, Y., Wahl, K., Crittenden, R. B., Bennett, M. L., Qi, L., Gong, C. C., Li, X. N., Barres, B. A., Bender, T. P., Ravichandran, K. S., Janes, K. A., Eberhart, C. G., & Zong, H. (2020). Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth. Cell, 180(3), 502-520.e19. https://doi.org/10.1016/j.cell.2019.12.024

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title = "Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth",

abstract = "The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression. Tumors shape a microenvironmental network by acting as a source of tumor-associated astrocytes that provide paracrine stimulation to microglia to secret IGF1, which is critical for tumor progression in SHH-activated mouse medulloblastoma models.",

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author = "Maojin Yao and Ventura, {P. Britten} and Ying Jiang and Rodriguez, {Fausto J.} and Lixin Wang and Perry, {Justin S.A.} and Yibo Yang and Kelsey Wahl and Crittenden, {Rowena B.} and Bennett, {Mariko L.} and Lin Qi and Gong, {Cong Cong} and Li, {Xiao Nan} and Barres, {Ben A.} and Bender, {Timothy P.} and Ravichandran, {Kodi S.} and Janes, {Kevin A.} and Eberhart, {Charles G.} and Hui Zong",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2020",

month = feb,

day = "6",

doi = "10.1016/j.cell.2019.12.024",

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Yao, M, Ventura, PB, Jiang, Y, Rodriguez, FJ, Wang, L, Perry, JSA, Yang, Y, Wahl, K, Crittenden, RB, Bennett, ML, Qi, L, Gong, CC, Li, XN, Barres, BA, Bender, TP, Ravichandran, KS, Janes, KA, Eberhart, CG & Zong, H 2020, 'Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth', Cell, vol. 180, no. 3, pp. 502-520.e19. https://doi.org/10.1016/j.cell.2019.12.024

TY - JOUR

T1 - Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth

AU - Yao, Maojin

AU - Ventura, P. Britten

AU - Jiang, Ying

AU - Rodriguez, Fausto J.

AU - Wang, Lixin

AU - Perry, Justin S.A.

AU - Yang, Yibo

AU - Wahl, Kelsey

AU - Crittenden, Rowena B.

AU - Bennett, Mariko L.

AU - Qi, Lin

AU - Gong, Cong Cong

AU - Li, Xiao Nan

AU - Barres, Ben A.

AU - Bender, Timothy P.

AU - Ravichandran, Kodi S.

AU - Janes, Kevin A.

AU - Eberhart, Charles G.

AU - Zong, Hui

PY - 2020/2/6

Y1 - 2020/2/6

N2 - The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression. Tumors shape a microenvironmental network by acting as a source of tumor-associated astrocytes that provide paracrine stimulation to microglia to secret IGF1, which is critical for tumor progression in SHH-activated mouse medulloblastoma models.

AB - The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression. Tumors shape a microenvironmental network by acting as a source of tumor-associated astrocytes that provide paracrine stimulation to microglia to secret IGF1, which is critical for tumor progression in SHH-activated mouse medulloblastoma models.

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KW - astrocytes

KW - brain tumor

KW - cellular network

KW - medulloblastoma

KW - microglia

KW - paracrine signaling

KW - trans-differentiation

KW - tumor microenvironment

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SP - 502-520.e19

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JF - Cell

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Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth

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