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
N1 - Funding Information:
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 .
Funding Information:
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.
Publisher Copyright:
© 2019 Elsevier Inc.
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.
KW - astrocytes
KW - brain tumor
KW - cellular network
KW - medulloblastoma
KW - microglia
KW - paracrine signaling
KW - TME
KW - trans-differentiation
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85078746595&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2019.12.024
DO - 10.1016/j.cell.2019.12.024
M3 - Article
C2 - 31983537
AN - SCOPUS:85078746595
VL - 180
SP - 502-520.e19
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -