Single-cell multiomics identifies clinically relevant mesenchymal stem-like cells and key regulators for MPNST malignancy.
Lai Man Natalie WuFeng ZhangRohit RaoMike AdamKai PollardSara SzaboXuezhao LiuKatie A BelcherZaili LuoSean OgurekColleen ReillyXin ZhouLi ZhangJoshua B RubinLong-Sheng ChangMei XinJiyang YuMario L SuvàChristine A PratilasSteven PotterQing Richard LuPublished in: Science advances (2022)
Malignant peripheral nerve sheath tumor (MPNST), a highly aggressive Schwann cell (SC)-derived soft tissue sarcoma, arises from benign neurofibroma (NF); however, the identity, heterogeneity and origins of tumor populations remain elusive. Nestin<sup>+</sup> cells have been implicated as tumor stem cells in MPNST; unexpectedly, single-cell profiling of human NF and MPNST and their animal models reveal a broad range of nestin-expressing SC lineage cells and dynamic acquisition of discrete cancer states during malignant transformation. We uncover a nestin-negative mesenchymal neural crest-like subpopulation as a previously unknown malignant stem-like state common to murine and human MPNSTs, which correlates with clinical severity. Integrative multiomics profiling further identifies unique regulatory networks and druggable targets against the malignant subpopulations in MPNST. Targeting key epithelial-mesenchymal transition and stemness regulators including ZEB1 and ALDH1A1 impedes MPNST growth. Together, our studies reveal the underlying principles of tumor cell-state evolution and their regulatory circuitries during NF-to-MPNST transformation, highlighting a hitherto unrecognized mesenchymal stem-like subpopulation in MPNST disease progression.
Keyphrases
- single cell
- stem cells
- rna seq
- epithelial mesenchymal transition
- signaling pathway
- induced apoptosis
- peripheral nerve
- high throughput
- endothelial cells
- bone marrow
- lps induced
- transcription factor
- oxidative stress
- cell cycle arrest
- pi k akt
- genome wide
- cell therapy
- nuclear factor
- transforming growth factor
- induced pluripotent stem cells
- inflammatory response
- mesenchymal stem cells
- cell proliferation
- gene expression
- papillary thyroid
- pluripotent stem cells
- cancer therapy
- cell death
- lymph node metastasis
- genetic diversity