Characterization of Wnt Signaling Pathway Aberrations in Metastatic Prostate Cancer.

IF 4.1 2区医学 Q2 CELL BIOLOGY

Molecular Cancer Research Pub Date : 2024-10-02 DOI:10.1158/1541-7786.MCR-24-0395

Sharon H Choi, Elizabeth Pan, Andrew Elliott, Himisha Beltran, Justine Panian, Christina Jamieson, Aditya Bagrodia, Brent Rose, Daniel Herchenhorn, Elisabeth Heath, Chadi Nabhan, Emmanuel S Antonarakis, Rana R McKay

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引用次数: 0

Abstract

Wnt (wingless-type) signaling pathway (WSP) alterations have been identified in patients with prostate cancer and are implicated in disease progression and hormonal resistance. In this study, we utilized a multi-institutional dataset to characterize molecular alterations in the canonical and noncanonical WSPs in prostate cancer. Patients with prostate cancer who underwent tissue-based genomic sequencing were investigated. Tumors with somatic activating mutations in CTNNB1 or RSPO2 or inactivating mutations in either APC or RNF43 were characterized as having aberrant canonical Wnt signaling (WSP-activated). Overall survival analyses were restricted to microsatellite-stable (MSS) tumors lacking RNF43 G659fs* mutations. We also investigated noncanonical WSP by evaluation of ROR1, ROR2, and WNT5 in WSP-activated versus WSP wild-type (WSP-WT) tumors. Of 4,138 prostate cancer samples, 3,684 were MSS. Among MSS tumors, 42.4% were from metastatic sites, of which 19.1% were WSP activated, and 57.6% were from the prostate, of which 10.1% were WSP activated. WSP-activated tumors were more prevalent in metastatic sites than in primary prostate cancer. WSP-activated prostate cancer exhibited more SPOP mutations and higher expression of canonical WSP activators than WSP-WT tumors. ROR1 gene expression was elevated in WSP-activated tumors from both primary and metastatic sites. M2 macrophages predominated the tumor microenvironment in WSP-activated tumors. There was no significant difference in overall survival between patients with WSP-activated and WSP-WT prostate cancer. WSP-activated prostate cancer demonstrated a more immunosuppressed tumor microenvironment and a pronounced upregulation of ROR1 gene expression, underscoring its potential involvement in the crosstalk between canonical and noncanonical WSPs. Implications: Our findings may provide a rationale for developing novel therapeutic strategies targeting Wnt-activated prostate cancer.

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转移性前列腺癌中 Wnt 信号通路畸变的特征。

在前列腺癌（PCa）患者中发现了 Wnt 信号通路（WSP）的改变，这些改变与疾病进展和激素抗性有关。我们利用一个多机构数据集来描述 PCa 中规范和非规范 WSP 的分子改变。我们对接受组织基因组测序的 PCa 患者进行了调查。CTNNB1 或 RSPO2 发生体细胞活化突变，或 APC 或 RNF43 发生失活突变的肿瘤被定性为具有异常规范 Wnt 信号转导（WSP 激活）。总生存期（OS）分析仅限于缺乏 RNF43 G659fs* 突变的微卫星稳定（MSS）肿瘤。我们还通过评估WSP激活与WSP野生型（WSP-WT）肿瘤中的ROR1、ROR2和WNT5，研究了非经典WSP。在 4,138 份 PCa 样本中，3,684 份为 MSS。在MSS肿瘤中，42.4%来自转移部位，其中19.1%为WSP激活肿瘤；57.6%来自前列腺，其中10.1%为WSP激活肿瘤。与原发性PCa相比，WSP激活的肿瘤在转移部位更为常见。与WSP-WT肿瘤相比，WSP激活型PCa表现出更多的SPOP突变和更高的典型WSP激活剂表达。在原发和转移部位的 WSP 激活肿瘤中，ROR1 基因表达均升高。在WSP激活的肿瘤中，M2巨噬细胞在肿瘤微环境中占主导地位。WSP激活型和WSP-WT型PCa患者的OS无明显差异。WSP激活的PCa表现出更强的免疫抑制肿瘤微环境和明显的ROR1基因表达上调，这强调了它可能参与了典型和非典型Wnt信号通路之间的串扰。影响：我们的研究结果可为开发针对 Wnt 激活型 PCa 的新型治疗策略提供依据。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer Research 医学-细胞生物学

CiteScore

9.90

自引率

0.00%

发文量

280

审稿时长

4-8 weeks

期刊介绍： Molecular Cancer Research publishes articles describing novel basic cancer research discoveries of broad interest to the field. Studies must be of demonstrated significance, and the journal prioritizes analyses performed at the molecular and cellular level that reveal novel mechanistic insight into pathways and processes linked to cancer risk, development, and/or progression. Areas of emphasis include all cancer-associated pathways (including cell-cycle regulation; cell death; chromatin regulation; DNA damage and repair; gene and RNA regulation; genomics; oncogenes and tumor suppressors; signal transduction; and tumor microenvironment), in addition to studies describing new molecular mechanisms and interactions that support cancer phenotypes. For full consideration, primary research submissions must provide significant novel insight into existing pathway functions or address new hypotheses associated with cancer-relevant biologic questions.