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Article
Filippo Giancotti
UT MD Anderson Cancer Center
Corresponding Author
ORCiD: https://orcid.org/0000-0002-0541-9519
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Unsupervised clustering and deconvolution analysis identifies a novel subtype of M-CRPC endowed with hybrid epithelial/mesenchymal (E/M) and luminal progenitor-like traits (Mesenchymal and Stem-like PC, MSPC). Analysis of patient datasets and mechanistic studies indicate that MSPC arises as a consequence of therapy-induced lineage plasticity. AR blockade instigates two separate and complementary processes: 1) transcriptional silencing of TP53 and hence acquisition of hybrid E/M and stem-like traits; and 2) inhibition of the BMP signaling, which promotes resistance to the pro-apoptotic and anti-proliferative effects of AR inhibition. The drug-tolerant prostate cancer cells generated through reprogramming are rescued by neuregulin and generate metastases in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibit efficacy in preclinical models of mixed ARPC/MSPC or MSPC, respectively. These results identify a novel subtype of M-CRPC, trace its origin to therapy-induced lineage plasticity, and reveal its dependency on HER2/3 signaling.
Keywords
prostate cancer, transcriptional inactivation, TP53, BMP pathway
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This is a list of supplementary files associated with this preprint. Click to download.
- SupplementaryTable1DEGsPCO94Clusters.xlsx
Supplementary Table 1
- SupplementaryTable2EnrichedGenesetsPCO94Clusters.xlsx
Supplementary Table 2
- SupplementaryTable3Top100GenesMCRPCSubtypes.xlsx
Supplementary Table 3
- SupplementaryTable4CustomGenesets.xlsx
Supplementary Table 4
- SupplementaryTable5ChEA3TFEnrichmentAnalysis.xlsx
Supplementary Table 5
- finalFigureS1FGcopy.pdf
- finalFigureS2FGcopy.pdf
- finalFigureS3FGcopy.pdf
- finalFigureS4HHcopy.pdf
- finalFigureS5HHcopy.pdf
- finalFigureS6HHcopy.pdf
- finalFigureS7HHcopy.pdf
- finalFigureS8HHcopy.pdf
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This is a preprint. It has not completed peer review.
Article
Filippo Giancotti
UT MD Anderson Cancer Center
Corresponding Author
ORCiD: https://orcid.org/0000-0002-0541-9519
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 05 May, 2021
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Unsupervised clustering and deconvolution analysis identifies a novel subtype of M-CRPC endowed with hybrid epithelial/mesenchymal (E/M) and luminal progenitor-like traits (Mesenchymal and Stem-like PC, MSPC). Analysis of patient datasets and mechanistic studies indicate that MSPC arises as a consequence of therapy-induced lineage plasticity. AR blockade instigates two separate and complementary processes: 1) transcriptional silencing of TP53 and hence acquisition of hybrid E/M and stem-like traits; and 2) inhibition of the BMP signaling, which promotes resistance to the pro-apoptotic and anti-proliferative effects of AR inhibition. The drug-tolerant prostate cancer cells generated through reprogramming are rescued by neuregulin and generate metastases in mice. Combined inhibition of HER2/3 and AR or mTORC1 exhibit efficacy in preclinical models of mixed ARPC/MSPC or MSPC, respectively. These results identify a novel subtype of M-CRPC, trace its origin to therapy-induced lineage plasticity, and reveal its dependency on HER2/3 signaling.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
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Figure 8
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