This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
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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There is NO Competing Interest.
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, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
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
Figure 7
Figure 8
There is NO Competing Interest.
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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