An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer

Davies, Alastair; Nouruzi, Shaghayegh; Ganguli, Dwaipayan; Namekawa, Takeshi; Thaper, Daksh; Linder, Simon; Karaoğlanoğlu, Fatih; Omur, Meltem E.; Kim, Soojin; Kobelev, Maxim; Kumar, Sahil; Sivak, Olena; Bostock, Chiara; Bishop, Jennifer; Hoogstraat, Marlous; Talal, Amina; Stelloo, Suzan; Poel, Henk van der; Bergman, Andries M.; Ahmed, Musaddeque; Fazli, Ladan; Huang, Haojie; Tilley, Wayne D.; Goodrich, David W.; Feng, Felix Y.; Gleave, Martin; He, Housheng Hansen; Hach, Faraz; Zwart, Wilbert; Beltran, Himisha; Selth, Luke A.; Zoubeidi, Amina

doi:10.1038/s41556-021-00743-5

Cited by 94 publications

(101 citation statements)

References 62 publications

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“…We have shown that basal CD44 Lo cancer cells spontaneously convert to a CD44 Hi cancer stem cell state in vitro and in vivo , in a ZEB1-dependent manner 14 . Consistent with further studies demonstrating that chemotherapy drives phenotypic plasticity 16, 36 , we show that all standard chemotherapies used to treat TNBC (Doxorubicin, Cisplatin and Docetaxel) drive CD44 Lo to CD44 Hi cell state transitions in a dose dependent manner (Fig. 3A; Supplementary Fig.…”

Section: Resultssupporting

confidence: 91%

Targeting phenotypic plasticity prevents metastasis and the development of chemotherapy-resistant disease

Juan

Hediyeh-Zadeh

Rangel

et al. 2022

Preprint

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Cancer cells invoke phenotypic plasticity programs to drive disease progression and evade chemotherapeutic insults, yet until now there have been no validated clinical therapies targeting this process. Here, we identify a phenotypic plasticity signature associated with poor survival in basal/triple-negative breast cancer, in which androgen signalling is prominent. We establish that anti-androgen therapies block cancer stem cell function and prevent chemotherapy-induced emergence of new cancer stem cells. In particular, the anti-androgen agent seviteronel synergizes with chemotherapy to improve chemotherapeutic inhibition of primary and metastatic tumour growth and prevent the emergence of chemotherapy-resistant disease. We validate cytoplasmic AR expression as a clinical phenotypic plasticity biomarker that predicts poor survival and poor response to chemotherapy, and positive response to seviteronel plus chemotherapy. This new targeted combination therapy validates modulating phenotypic plasticity as an effective strategy to prevent and treat chemotherapy-resistant cancers with transformative clinical potential.

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Section: Resultssupporting

confidence: 91%

Targeting phenotypic plasticity prevents metastasis and the development of chemotherapy-resistant disease

Juan

Hediyeh-Zadeh

Rangel

et al. 2022

Preprint

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“…Although EZH2 has been shown to regulate a transcriptional program driving a lineage-switch away from differentiated adenocarcinoma in RB1 -/- , TP53 -/- models (Davies et al, 2021; Ping Mu et al, 2017; Sheng Yu Ku et al, 2017), we observed only an insignificant increase in AR-positivity in both PC35-1 and PC35-2 in the EZH2i condition (Figure S7C), and we did not see upregulation of EZH2 or phosho-EZH2 upon enzalutamide treatment (Figure S7D), suggesting context-dependence for EZH2-driven mechanisms observed in RB1/TP53 loss models. Together these results indicate that the stem-like/progenitor subpopulation can be directly targeted by AURKAi to block growth and imply the existence of a residual AR POS proliferative population with potential sensitivity to AR inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…Diversified and labile transcriptional programs within a heterogenous tumor cell population can rapidly confer clonal fitness in the face of therapeutic pressure (Bolis et al, 2021; Davies et al, 2021; Fennell et al, 2021; Taavitsainen et al, 2021). In our models clonally-determined lineage distributions were partially explained by pre-existing genomic alterations.…”

Section: Discussionmentioning

confidence: 99%

The origin and dynamics of cellular heterogeneity vary across lineage subtypes of castrate resistant prostate cancer

Beshiri

Capaldo

Lake

et al. 2022

Preprint

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To resist lineage-dependent therapies, cancer cells adopt a plastic stem-like state, leading to phenotypic heterogeneity. Here we dissect the cellular origins of such heterogeneity in a metastatic castration-resistant prostate cancer (CRPC) patient-derived adenocarcinoma organoid model displaying a range of luminal and neuroendocrine phenotypes and driven by mutations in cell cycle (CDKN1B) and epigenetic (ARID1A, and ARID1B) regulators. As shown by lineage tracing, metastatic tumor heterogeneity originated from distinct subclones of infrequent stem/progenitor cells that each produced a full distribution of differentiated lineage markers, suggesting multiclonal evolution to a relatively stable bipotential state. Single cell ATAC-seq analyses revealed the co-occurrence of transcription factor activities associated with multiple disparate lineages in the stem/progenitors: WNT and RXR stem factors, AR and FOXA1 luminal epithelial drivers, and NR2F1 and ASCL1 neural factors. Inhibition of AR in combination with AURKA but not EZH2 blocked tumor growth. These data provide insight into the origins and dynamics of cancer cell plasticity and stem targeted therapy.

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“…Once bound to DNA, the AR recruits chromatin-modifying enzymes that stabilize accessibility and provide a platform for coregulators and TFs [ 91 ]. This includes histone methyltransferases such as EZH2 [ 92 , 93 , 94 ], SET9 [ 95 ], and MLL complex (MLL, MLL4, WDR5, ASH2L) [ 96 ]; histone acetyltransferases (HAT) such as p160, SRC-1, TIF2/GRIP1-1, ACTR/AIB1/RAC3/pCIP [ 97 , 98 , 99 , 100 , 101 ], CBP [ 102 ], p300 [ 103 ], and pCAF [ 104 ]; and histone deacetylases (HDAC) such as HDAC1-3 (class I), HDAC4-10 (class II), and SIRT1-7 (class III) and HDAC11 (class IV) [ 105 ]. Characterization of the AREIII enhancer demonstrated the sequential recruitment of p160 and p300, was then followed by CBP and pCAF [ 21 ].…”

Section: Impact Of Chromatin Modifying Enzymes On Ar Activitymentioning

confidence: 99%

Androgen Receptor-Mediated Transcription in Prostate Cancer

Özturan

Morova

Lack

2022

Cells

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Androgen receptor (AR)-mediated transcription is critical in almost all stages of prostate cancer (PCa) growth and differentiation. This process involves a complex interplay of coregulatory proteins, chromatin remodeling complexes, and other transcription factors that work with AR at cis-regulatory enhancer regions to induce the spatiotemporal transcription of target genes. This enhancer-driven mechanism is remarkably dynamic and undergoes significant alterations during PCa progression. In this review, we discuss the AR mechanism of action in PCa with a focus on how cis-regulatory elements modulate gene expression. We explore emerging evidence of genetic variants that can impact AR regulatory regions and alter gene transcription in PCa. Finally, we highlight several outstanding questions and discuss potential mechanisms of this critical transcription factor.

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An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer

Cited by 94 publications

References 62 publications

Targeting phenotypic plasticity prevents metastasis and the development of chemotherapy-resistant disease

Targeting phenotypic plasticity prevents metastasis and the development of chemotherapy-resistant disease

The origin and dynamics of cellular heterogeneity vary across lineage subtypes of castrate resistant prostate cancer

Androgen Receptor-Mediated Transcription in Prostate Cancer

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