Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model
Neurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely but nearly always include the development of cutaneous, plexiform and diffuse neurofibromas that are managed over many years. Recent...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-09-01
|
| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1253659/full |
| _version_ | 1827807161529401344 |
|---|---|
| author | Dalton T. McLean Dalton T. McLean Jennifer J. Meudt Loren D. Lopez Rivera Dominic T. Schomberg Derek M. Pavelec Tyler T. Duellman Darya G. Buehler Patrick B. Schwartz Patrick B. Schwartz Melissa Graham Laura M. Lee Keri D. Graff Jamie L. Reichert Sandra S. Bon-Durant Charles M. Konsitzke Sean M. Ronnekleiv-Kelly Dhanansayan Shanmuganayagam Dhanansayan Shanmuganayagam Dhanansayan Shanmuganayagam Dhanansayan Shanmuganayagam C. Dustin Rubinstein |
| author_facet | Dalton T. McLean Dalton T. McLean Jennifer J. Meudt Loren D. Lopez Rivera Dominic T. Schomberg Derek M. Pavelec Tyler T. Duellman Darya G. Buehler Patrick B. Schwartz Patrick B. Schwartz Melissa Graham Laura M. Lee Keri D. Graff Jamie L. Reichert Sandra S. Bon-Durant Charles M. Konsitzke Sean M. Ronnekleiv-Kelly Dhanansayan Shanmuganayagam Dhanansayan Shanmuganayagam Dhanansayan Shanmuganayagam Dhanansayan Shanmuganayagam C. Dustin Rubinstein |
| author_sort | Dalton T. McLean |
| collection | DOAJ |
| description | Neurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely but nearly always include the development of cutaneous, plexiform and diffuse neurofibromas that are managed over many years. Recent single-cell transcriptomics profiling efforts of neurofibromas have begun to reveal cell signaling processes. However, the cell signaling networks in mature, non-cutaneous neurofibromas remain unexplored. Here, we present insights into the cellular composition and signaling within mature neurofibromas, contrasting with normal adjacent tissue, in a porcine model of NF1 using single-cell RNA sequencing (scRNA-seq) analysis and histopathological characterization. These neurofibromas exhibited classic diffuse-type histologic morphology and expected patterns of S100, SOX10, GFAP, and CD34 immunohistochemistry. The porcine mature neurofibromas closely resemble human neurofibromas histologically and contain all known cellular components of their human counterparts. The scRNA-seq confirmed the presence of all expected cell types within these neurofibromas and identified novel populations of fibroblasts and immune cells, which may contribute to the tumor microenvironment by suppressing inflammation, promoting M2 macrophage polarization, increasing fibrosis, and driving the proliferation of Schwann cells. Notably, we identified tumor-associated IDO1+/CD274+ (PD-L1)+ dendritic cells, which represent the first such observation in any NF1 animal model and suggest the role of the upregulation of immune checkpoints in mature neurofibromas. Finally, we observed that cell types in the tumor microenvironment are poised to promote immune evasion, extracellular matrix reconstruction, and nerve regeneration. |
| first_indexed | 2024-03-11T21:52:13Z |
| format | Article |
| id | doaj.art-0f275dea337648fba3fdc744507e7930 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-11T21:52:13Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-0f275dea337648fba3fdc744507e79302023-09-26T07:00:39ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-09-011310.3389/fonc.2023.12536591253659Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine modelDalton T. McLean0Dalton T. McLean1Jennifer J. Meudt2Loren D. Lopez Rivera3Dominic T. Schomberg4Derek M. Pavelec5Tyler T. Duellman6Darya G. Buehler7Patrick B. Schwartz8Patrick B. Schwartz9Melissa Graham10Laura M. Lee11Keri D. Graff12Jamie L. Reichert13Sandra S. Bon-Durant14Charles M. Konsitzke15Sean M. Ronnekleiv-Kelly16Dhanansayan Shanmuganayagam17Dhanansayan Shanmuganayagam18Dhanansayan Shanmuganayagam19Dhanansayan Shanmuganayagam20C. Dustin Rubinstein21Biotechnology Center, University of Wisconsin–Madison, Madison, WI, United StatesMolecular & Environmental Toxicology Program, University of Wisconsin–Madison, Madison, WI, United StatesBiomedical & Genomic Research Group, Department of Animal and Dairy Sciences, University of Wisconsin–Madison, Madison, WI, United StatesMolecular & Environmental Toxicology Program, University of Wisconsin–Madison, Madison, WI, United StatesBiomedical & Genomic Research Group, Department of Animal and Dairy Sciences, University of Wisconsin–Madison, Madison, WI, United StatesBiotechnology Center, University of Wisconsin–Madison, Madison, WI, United StatesBiotechnology Center, University of Wisconsin–Madison, Madison, WI, United StatesDepartment of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United StatesMolecular & Environmental Toxicology Program, University of Wisconsin–Madison, Madison, WI, United StatesDepartment of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United StatesResearch Animal Resources and Compliance (RARC), Office of the Vice Chancellor for Research and Graduate Education, University of Wisconsin–Madison, Madison, WI, United StatesResearch Animal Resources and Compliance (RARC), Office of the Vice Chancellor for Research and Graduate Education, University of Wisconsin–Madison, Madison, WI, United StatesSwine Research and Teaching Center, Department of Animal and Dairy Sciences, University of Wisconsin–Madison, Madison, WI, United StatesSwine Research and Teaching Center, Department of Animal and Dairy Sciences, University of Wisconsin–Madison, Madison, WI, United StatesBiotechnology Center, University of Wisconsin–Madison, Madison, WI, United StatesBiotechnology Center, University of Wisconsin–Madison, Madison, WI, United StatesDepartment of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United StatesMolecular & Environmental Toxicology Program, University of Wisconsin–Madison, Madison, WI, United StatesBiomedical & Genomic Research Group, Department of Animal and Dairy Sciences, University of Wisconsin–Madison, Madison, WI, United StatesDepartment of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United StatesCenter for Biomedical Swine Research and Innovation, University of Wisconsin–Madison, Madison, WI, United StatesBiotechnology Center, University of Wisconsin–Madison, Madison, WI, United StatesNeurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely but nearly always include the development of cutaneous, plexiform and diffuse neurofibromas that are managed over many years. Recent single-cell transcriptomics profiling efforts of neurofibromas have begun to reveal cell signaling processes. However, the cell signaling networks in mature, non-cutaneous neurofibromas remain unexplored. Here, we present insights into the cellular composition and signaling within mature neurofibromas, contrasting with normal adjacent tissue, in a porcine model of NF1 using single-cell RNA sequencing (scRNA-seq) analysis and histopathological characterization. These neurofibromas exhibited classic diffuse-type histologic morphology and expected patterns of S100, SOX10, GFAP, and CD34 immunohistochemistry. The porcine mature neurofibromas closely resemble human neurofibromas histologically and contain all known cellular components of their human counterparts. The scRNA-seq confirmed the presence of all expected cell types within these neurofibromas and identified novel populations of fibroblasts and immune cells, which may contribute to the tumor microenvironment by suppressing inflammation, promoting M2 macrophage polarization, increasing fibrosis, and driving the proliferation of Schwann cells. Notably, we identified tumor-associated IDO1+/CD274+ (PD-L1)+ dendritic cells, which represent the first such observation in any NF1 animal model and suggest the role of the upregulation of immune checkpoints in mature neurofibromas. Finally, we observed that cell types in the tumor microenvironment are poised to promote immune evasion, extracellular matrix reconstruction, and nerve regeneration.https://www.frontiersin.org/articles/10.3389/fonc.2023.1253659/fullneurofibromatosis type 1 (NF1)single cell RNA seqswinetumor microenvironment (TME)neurofibromacancer-associated fibroblasts (CAF) |
| spellingShingle | Dalton T. McLean Dalton T. McLean Jennifer J. Meudt Loren D. Lopez Rivera Dominic T. Schomberg Derek M. Pavelec Tyler T. Duellman Darya G. Buehler Patrick B. Schwartz Patrick B. Schwartz Melissa Graham Laura M. Lee Keri D. Graff Jamie L. Reichert Sandra S. Bon-Durant Charles M. Konsitzke Sean M. Ronnekleiv-Kelly Dhanansayan Shanmuganayagam Dhanansayan Shanmuganayagam Dhanansayan Shanmuganayagam Dhanansayan Shanmuganayagam C. Dustin Rubinstein Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model Frontiers in Oncology neurofibromatosis type 1 (NF1) single cell RNA seq swine tumor microenvironment (TME) neurofibroma cancer-associated fibroblasts (CAF) |
| title | Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model |
| title_full | Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model |
| title_fullStr | Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model |
| title_full_unstemmed | Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model |
| title_short | Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model |
| title_sort | single cell rna sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model |
| topic | neurofibromatosis type 1 (NF1) single cell RNA seq swine tumor microenvironment (TME) neurofibroma cancer-associated fibroblasts (CAF) |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1253659/full |
| work_keys_str_mv | AT daltontmclean singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT daltontmclean singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT jenniferjmeudt singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT lorendlopezrivera singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT dominictschomberg singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT derekmpavelec singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT tylertduellman singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT daryagbuehler singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT patrickbschwartz singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT patrickbschwartz singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT melissagraham singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT lauramlee singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT keridgraff singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT jamielreichert singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT sandrasbondurant singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT charlesmkonsitzke singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT seanmronnekleivkelly singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT dhanansayanshanmuganayagam singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT dhanansayanshanmuganayagam singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT dhanansayanshanmuganayagam singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT dhanansayanshanmuganayagam singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel AT cdustinrubinstein singlecellrnasequencingofneurofibromasrevealsatumormicroenvironmentfavorableforneuralregenerationandimmunesuppressioninaneurofibromatosistype1porcinemodel |