Pre-existing Castration-resistant Prostate Cancer–like Cells in Primary Prostate Cancer Promote Resistance to Hormonal Therapy

Cheng, Qing; Butler, Wayne M.; Zhou, Yinglu; Zhang, Hong; Tang, Lu; Perkinson, Kathryn; Chen, Xufeng; Jiang, Xiaoyin Sara; McCall, Shannon J.; Inman, Brant A.; Huang, Jiaoti

doi:10.1016/j.eururo.2021.12.039

Cited by 72 publications

(66 citation statements)

References 40 publications

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“…However, the molecular mechanism that promotes lineage plasticity in many mCRPC subtypes, especially in the context of TP53/RB1 deficiency, is not fully understood. Furthermore, although heterogenous subpopulations have been connected to prostate cancer (PCa) progression and AR therapy resistance [19][20][21][22][23][24] , the key survival factor of lineage-plastic and stem-like cells has yet to be defined. Finally, therapeutic approaches targeting lineage plasticity-driven resistance are not currently available, underscoring the unmet clinical urgency to identify druggable targets that drive lineage plasticity.…”

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confidence: 99%

Ectopic JAK–STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance

Deng

Wang

et al. 2022

Nat Cancer

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Emerging evidence indicates that various cancers can gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic aberrations correlate with lineage plasticity, the molecular mechanisms enabling the acquisition of lineage plasticity have not been fully elucidated. We reveal that Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling is a crucial executor in promoting lineage plasticity-driven androgen receptor (AR)-targeted therapy resistance in prostate cancer. Importantly, ectopic JAK–STAT activation is specifically required for the resistance of stem-like subclones expressing multilineage transcriptional programs but not subclones exclusively expressing the neuroendocrine-like lineage program. Both genetic and pharmaceutical inhibition of JAK–STAT signaling resensitizes resistant tumors to AR-targeted therapy. Together, these results suggest that JAK–STAT are compelling therapeutic targets for overcoming lineage plasticity-driven AR-targeted therapy resistance.

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confidence: 99%

Ectopic JAK–STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance

Deng

Wang

et al. 2022

Nat Cancer

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“…Here we identify tumor cells with castration-resistant potential present already before treatment and not as the result of evolutionary selection during ADT. Another study also shows that pre-existing castration-resistant PCa-cells exist in primary prostate cancer exists 131 .…”

Section: Discussionmentioning

confidence: 91%

Spatio-temporal analysis of prostate tumors in situ suggests pre-existence of treatment-resistant clones

et al. 2022

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The molecular mechanisms underlying lethal castration-resistant prostate cancer remain poorly understood, with intratumoral heterogeneity a likely contributing factor. To examine the temporal aspects of resistance, we analyze tumor heterogeneity in needle biopsies collected before and after treatment with androgen deprivation therapy. By doing so, we are able to couple clinical responsiveness and morphological information such as Gleason score to transcriptome-wide data. Our data-driven analysis of transcriptomes identifies several distinct intratumoral cell populations, characterized by their unique gene expression profiles. Certain cell populations present before treatment exhibit gene expression profiles that match those of resistant tumor cell clusters, present after treatment. We confirm that these clusters are resistant by the localization of active androgen receptors to the nuclei in cancer cells post-treatment. Our data also demonstrates that most stromal cells adjacent to resistant clusters do not express the androgen receptor, and we identify differentially expressed genes for these cells. Altogether, this study shows the potential to increase the power in predicting resistant tumors.

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“…Frequently, these subsets or clusters display distinct cellular functionalities and share commonly altered signaling pathways. For druggable pathways, translational researchers have therefore identified therapeutic implications in various cancers, e.g., RCC [ 23 ] and prostate cancer [ 43 ]. Notably, clustering approaches for the methylomic data of pediatric brain tumors already play a prominent role in the clinical routine by allowing further subtyping of cancer specimens [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Visual Clustering of Transcriptomic Data from Primary and Metastatic Tumors—Dependencies and Novel Pitfalls

Marquardt

Kollmannsberger

Krebs

et al. 2022

Genes

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Personalized oncology is a rapidly evolving area and offers cancer patients therapy options that are more specific than ever. However, there is still a lack of understanding regarding transcriptomic similarities or differences of metastases and corresponding primary sites. Applying two unsupervised dimension reduction methods (t-Distributed Stochastic Neighbor Embedding (t-SNE) and Uniform Manifold Approximation and Projection (UMAP)) on three datasets of metastases (n = 682 samples) with three different data transformations (unprocessed, log10 as well as log10 + 1 transformed values), we visualized potential underlying clusters. Additionally, we analyzed two datasets (n = 616 samples) containing metastases and primary tumors of one entity, to point out potential familiarities. Using these methods, no tight link between the site of resection and cluster formation outcome could be demonstrated, or for datasets consisting of solely metastasis or mixed datasets. Instead, dimension reduction methods and data transformation significantly impacted visual clustering results. Our findings strongly suggest data transformation to be considered as another key element in the interpretation of visual clustering approaches along with initialization and different parameters. Furthermore, the results highlight the need for a more thorough examination of parameters used in the analysis of clusters.

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Pre-existing Castration-resistant Prostate Cancer–like Cells in Primary Prostate Cancer Promote Resistance to Hormonal Therapy

Cited by 72 publications

References 40 publications

Ectopic JAK–STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance

Ectopic JAK–STAT activation enables the transition to a stem-like and multilineage state conferring AR-targeted therapy resistance

Spatio-temporal analysis of prostate tumors in situ suggests pre-existence of treatment-resistant clones

Visual Clustering of Transcriptomic Data from Primary and Metastatic Tumors—Dependencies and Novel Pitfalls

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