Hyperactive mTOR induces neuroendocrine differentiation in prostate cancer cell with concurrent up‐regulation of IRF1

Kanayama, Mayuko; Hayano, Toshiya; Koebis, Michinori; Maeda, Tatsuya; Tabe, Yoko; Horie, Shigeo; Aiba, Atsu

doi:10.1002/pros.23425

Cited by 13 publications

(13 citation statements)

References 42 publications

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“…To further confirm this mechanism in an alternative cell line, we treated C4-2B cells with enzalutamide in the presence of conditioned media from wild type mouse fibroblasts or CRISPR/Cas9 CD105-knockout mouse fibroblasts to measure the expression of the neuroendocrine differentiation gene panel (p < 0.0001, Fig 4E, Supplemental Figure S3). After confirming this mechanism at the transcriptional level, 22Rv1 were again treated with conditioned medium from CAF nucleofected with siRNA against SFRP1 compared to scramble control, which resulted in elevated mTOR phosphorylation (Ser 2448, associated with mTORC1 activation) ( Fig 4F) [27,28]. Furthermore, 22Rv1 were treated with combinations of recombinant SFRP1 and/or an mTOR inhibitor, rapamycin.…”

Section: Stromal Cd105 Mediated Sfrp1 Induced Pca Neuroendocrine Diffmentioning

confidence: 81%

Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner

et al. 2018

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Heterogeneous prostatic carcinoma-associated fibroblasts (CAF) contribute to tumor progression and resistance to androgen signaling deprivation therapy (ADT). CAF subjected to extended passaging, compared to low passage CAF, were found to lose tumor expansion potential and heterogeneity. Cell surface endoglin (CD105), known to be expressed on proliferative endothelia and mesenchymal stem cells, was diminished in high passage CAF. RNA-sequencing revealed SFRP1 to be distinctly expressed by tumor-inductive CAF, which was further demonstrated to occur in a CD105-dependent manner. Moreover, ADT resulted in further expansion of the CD105 fibroblastic population and downstream SFRP1 in 3-dimensional cultures and patient-derived xenograft tissues. In patients, CD105 fibroblasts were found to circumscribe epithelia with neuroendocrine differentiation. CAF-derived SFRP1, driven by CD105 signaling, was necessary and sufficient to induce prostate cancer neuroendocrine differentiation in a paracrine manner. A partially humanized CD105 neutralizing antibody, TRC105, inhibited fibroblastic SFRP1 expression and epithelial neuroendocrine differentiation. In a novel synthetic lethality paradigm, we found that simultaneously targeting the epithelia and its microenvironment with ADT and TRC105, respectively, reduced castrate-resistant tumor progression, in a model where either ADT or TRC105 alone had little effect.

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Section: Stromal Cd105 Mediated Sfrp1 Induced Pca Neuroendocrine Diffmentioning

confidence: 81%

Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner

et al. 2018

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“…It is known that glutamine sensing triggers mTOR activity (52,53). mTOR signaling is associated with PCa neuroendocrine differentiation (28,54,55). Therefore, we reasoned that Table 1).…”

Section: Methodsmentioning

confidence: 99%

Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming

Mishra

Haldar

Placencio

et al. 2018

Journal of Clinical Investigation

116

110

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Prostate cancer is an androgen-dependent disease subject to interactions between the tumor epithelium and its microenvironment. Here, we found that epigenetic changes in prostatic cancer-associated fibroblasts (CAF) initiated a cascade of stromal-epithelial interactions. This facilitated lethal prostate cancer growth and development of resistance to androgen signaling deprivation therapy (ADT). We identified a Ras inhibitor, RASAL3, as epigenetically silenced in human prostatic CAF, leading to oncogenic Ras activity driving macropinocytosis-mediated glutamine synthesis. Interestingly, ADT further promoted RASAL3 epigenetic silencing and glutamine secretion by prostatic fibroblasts. In an orthotopic xenograft model, subsequent inhibition of macropinocytosis and glutamine transport resulted in antitumor effects. Stromal glutamine served as a source of energy through anaplerosis and as a mediator of neuroendocrine differentiation for prostate adenocarcinoma. Antagonizing the uptake of glutamine restored sensitivity to ADT in a castration-resistant xenograft model. In validating these findings, we found that prostate cancer patients on ADT with therapeutic resistance had elevated blood glutamine levels compared with those with therapeutically responsive disease (odds ratio = 7.451, P = 0.02). Identification of epigenetic regulation of Ras activity in prostatic CAF revealed RASAL3 as a sensor for metabolic and neuroendocrine reprogramming in prostate cancer patients failing ADT.

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“…However, in the PDXs used in our studies, MYCN was highly expressed by BCaP-1, LVCaP-3, and LgCaP-1, and despite no AR expression, these cells did not exhibit NEPC characteristics. Hyperactive mTOR is reported to induce NE differentiation in vitro in LNCaP cells with the concurrent upregulation of IFN regulatory factor 1 and the downregulation of ARS associated with the upregulation of CDKN1A (also known as p21) and growth arrest ( 65 ). However, all of the AR – PDXs reported herein expressed a high level of p21, but only a subset underwent NE differentiation and none were growth arrested.…”

Section: Discussionmentioning

confidence: 99%

Resistance to androgen receptor signaling inhibition does not necessitate development of neuroendocrine prostate cancer

Brennen¹,

Zhu²,

Coleman³

et al. 2021

JCI Insight

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Resistance to AR signaling inhibitors (ARSis) in a subset of metastatic castration-resistant prostate cancers (mCRPCs) occurs with the emergence of AR – neuroendocrine prostate cancer (NEPC) coupled with mutations/deletions in PTEN , TP53 , and RB1 and the overexpression of DNMTs, EZH2, and/or SOX2. To resolve whether the lack of AR is the driving factor for the emergence of the NE phenotype, molecular, cell, and tumor biology analyses were performed on 23 xenografts derived from patients with PC, recapitulating the full spectrum of genetic alterations proposed to drive NE differentiation. Additionally, phenotypic response to CRISPR/Cas9-mediated AR KO in AR + CRPC cells was evaluated. These analyses document that (a) ARSi-resistant NEPC developed without androgen deprivation treatment; (b) ARS in ARSi-resistant AR + /NE + double-positive “amphicrine” mCRPCs did not suppress NE differentiation; (c) the lack of AR expression did not necessitate acquiring a NE phenotype, despite concomitant mutations/deletions in PTEN and TP53 , and the loss of RB1 but occurred via emergence of an AR – /NE – double-negative PC (DNPC); (d) despite DNPC cells having homogeneous genetic driver mutations, they were phenotypically heterogeneous, expressing basal lineage markers alone or in combination with luminal lineage markers; and (e) AR loss was associated with AR promoter hypermethylation in NEPCs but not in DNPCs.

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Hyperactive mTOR induces neuroendocrine differentiation in prostate cancer cell with concurrent up‐regulation of IRF1

Abstract: We identified active mTOR as a novel inducer of NED, and elucidated a mechanism underlying the malignant transformation of NEPCa by recapitulating NED in vitro.

Cited by 13 publications

References 42 publications

Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner

Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner

Stromal epigenetic alterations drive metabolic and neuroendocrine prostate cancer reprogramming

Resistance to androgen receptor signaling inhibition does not necessitate development of neuroendocrine prostate cancer

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