EGFR as a stable marker of prostate cancer dissemination to bones

Nastały, Paulina; Stoupiec, Sara; Popęda, Marta; Smentoch, Julia; Schlomm, Thorsten; Morrissey, Colm; Żaczek, Anna; Tennstedt, Pierre; Graefen, Markus; Eltze, Elke; Maiuri, Paolo; Semjonow, Axel; Pantel, Klaus; Brandt, Burkhard; Bednarz‐Knoll, Natalia

doi:10.1038/s41416-020-01052-8

Cited by 31 publications

(21 citation statements)

References 40 publications

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“…3; c-Met: p=0.0053; p4EBP1: p=0.0019; pS6 p=0.0386). Increased c-Met and EGFR expression in bone metastases compared with primary prostate cancer, identified using the single cell mass cytometry, is consistent with previously reported findings 33,34 . This serves as additional confirmation of the specificity of the antibody panel used for single cell proteomic analysis of prostate cancer cells residing within the various tissue compartments.…”

Section: Main Textsupporting

confidence: 92%

Single cell proteomics of tumor compartments identifies differential kinase activities defining sensitivity to mTOR-PI3-kinase inhibition

Karabacak

Zheng

Dubash

et al. 2021

Preprint

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Cancer therapy often results in heterogeneous responses in different metastatic lesions in the same patient. Inter- and intra-tumor heterogeneity in proteomic signaling within the various tumor compartments and its impact on therapy are not well characterized due to the limited sensitivity of single cell proteomic approaches. To overcome this barrier, we applied single cell mass cytometry with a customized 29-antibody panel [against cell states, receptor tyrosine kinases (RTK) and phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR)-, mitogen-activated protein kinase (MAPK)-, and cytokine-signaling] to PTEN-deleted orthotopic prostate cancer xenograft models to measure the evolution of kinase activities in different tumor compartments during metastasis and upon drug treatment. Compared with primary tumors and circulating tumor cells (CTCs), bone metastases but not lung and liver metastases exhibited elevated PI3K/mTOR signaling and RTKs including c-Met protein, which, when suppressed, impaired tumor growth in the bone. Intra-tumoral heterogeneity within tumor compartments also arises from highly proliferative EpCAMhigh epithelial cells with increased PI3K and mTOR kinase activities co-existing with poorly proliferating EpCAMlow mesenchymal populations with reduced kinase activities, findings recapitulated in epithelial and mesenchymal CTC populations in metastatic prostate and breast cancer patients. Increased kinase activity in EpCAMhigh cells rendered them more sensitive to PI3K/mTOR inhibition and drug resistant EpCAMlow populations with reduced kinase activity emerged over time. Taken together, single cell proteomics identified microenvironment- and cell state-dependent activation of kinase networks creating heterogeneity and differential drug sensitivity among and within tumor populations across different sites, defining a new paradigm of drug responses to kinase inhibitors.

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Section: Main Textsupporting

confidence: 92%

Single cell proteomics of tumor compartments identifies differential kinase activities defining sensitivity to mTOR-PI3-kinase inhibition

Karabacak

Zheng

Dubash

et al. 2021

Preprint

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“…Even more, castration leads to an increase in EGFR expression [96]. Supporting this crosstalk between AR and EGFR, several studies have found a significant relationship between EGFR expression and PCa progression [96][97][98][99][100][101][102]. In this study, no correlation was found in this direction.…”

Section: ãããmentioning

confidence: 49%

KRAS, BRAF, PIK3CA mutation frequency of radical prostatectomy samples and review of the literature

et al. 2020

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Objective: The molecular basis of prostate cancer is highly heterogeneous. Our study aimed to perform the mutation analysis of KRAS, BRAF, PIK3CA, and immunohistochemical (IHC) evaluation of EGFR, HER2, p16, and PTEN to demonstrate new areas for targeted therapies. Methods: A total of 24 prostatectomy samples diagnosed with adenocarcinoma were analyzed by microarray hybridization. Also, these samples were IHC stained for EGFR, HER2, P16, and PTEN. The cases were divided into two groups based on low and high Gleason scores. All findings were compared with the clinicopathological parameters of the patients. Results: While KRAS mutation was in 3/24 (12.5%) of our cases, BRAF and PIK3CA mutations were not detected. There was no significant difference between the groups in terms of KRAS mutation frequency. HER2 was immunohistochemically negative in all samples. There was no correlation between EGFR, P16 immunopositivity, and clinicopathological features. Conclusion: KRAS mutation frequency is similar to those in Asian populations. BRAF and PIK3CA mutation frequencies have been reported in the literature in the range of 0-15% and 0-10.4%, respectively, consistent with our study findings. HER2 immunoexpression is a controversial issue in the literature. EGFR and p16 expressions may not correlate with the stage.

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“…Upregulation of EGFR has been associated with prostate cancer progression and metastasis using various prostate cancer cell line model systems (DU145, PC-3, LNCaP and C4-2B) ( Gan et al, 2010 ; Day et al, 2017 ). Primary tumour EGFR overexpression correlated with migratory and metastatic phenotype of tumour cells in prostate cancer patients ( Nastały et al, 2020 ). While CTCs were detected in only 13% (5/39) of high-risk patients in this study, all CTCs were positive for EGFR using immunocytochemistry ( Nastały et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

Circulating Tumour Cells Indicate the Presence of Residual Disease Post-Castration in Prostate Cancer Patient-Derived Xenograft Models

Hassan

Blick

Wood

et al. 2022

Front. Cell Dev. Biol.

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Castrate-resistant prostate cancer (CRPC) is the lethal form of prostate cancer. Epithelial mesenchymal plasticity (EMP) has been associated with disease progression to CRPC, and prostate cancer therapies targeting the androgen signalling axis, including androgen deprivation therapy (ADT), promote EMP. We explored effects of castration on EMP in the tumours and circulating tumour cells (CTCs) of patient-derived xenograft (PDX)-bearing castrated mice using human-specific RT-qPCR assays and immunocytochemistry. Expression of prostate epithelial cell marker KLK3 was below detection in most tumours from castrated mice (62%, 23/37 mice), consistent with its known up-regulation by androgens. Endpoint tumour size after castration varied significantly in a PDX model-specific pattern; while most tumours were castration-sensitive (BM18, LuCaP70), the majority of LuCaP105 tumours continued to grow following castration. By contrast, LuCaP96 PDX showed a mixed response to castration. CTCs were detected in 33% of LuCaP105, 43% of BM18, 47% of LuCaP70, and 54% of LuCaP96 castrated mice using RPL32 mRNA measurement in plasma. When present, CTC numbers estimated using human RPL32 expression ranged from 1 to 458 CTCs per ml blood, similar to our previous observations in non-castrated mice. In contrast to their non-castrated counterparts, there was no relationship between tumour size and CTC burden in castrated mice. Unsupervised hierarchical clustering of the gene expression profiles of CTCs collected from castrated and non-castrated mice revealed distinct CTC sub-groups within the pooled population that were classified as having mesenchymal, epithelial, or EMP hybrid gene expression profiles. The epithelial signature was only found in CTCs from non-castrated mice. Hybrid and mesenchymal signatures were detected in CTCs from both castrated and non-castrated mice, with an emphasis towards mesenchymal phenotypes in castrated mice. Post-castration serum PSA levels were either below detection or very low for all the CTC positive samples highlighting the potential usefulness of CTCs for disease monitoring after androgen ablation therapy. In summary, our study of castration effects on prostate cancer PDX CTCs showed that CTCs were often detected in the castrate setting, even in mice with no palpable tumours, and demonstrated the superior ability of CTCs to reveal residual disease over the conventional clinical biomarker serum PSA.

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EGFR as a stable marker of prostate cancer dissemination to bones

Cited by 31 publications

References 40 publications

Single cell proteomics of tumor compartments identifies differential kinase activities defining sensitivity to mTOR-PI3-kinase inhibition

Single cell proteomics of tumor compartments identifies differential kinase activities defining sensitivity to mTOR-PI3-kinase inhibition

KRAS, BRAF, PIK3CA mutation frequency of radical prostatectomy samples and review of the literature

Circulating Tumour Cells Indicate the Presence of Residual Disease Post-Castration in Prostate Cancer Patient-Derived Xenograft Models

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