University of California San Diego, San Diego, California.
Department of Medical Affairs and Precision Oncology Alliance, Caris Life Sciences, Phoenix, Arizona.
Mol Cancer Res. 2024 Oct 2;22(10):920-931. doi: 10.1158/1541-7786.MCR-24-0395.
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.
Wnt（无翅型）信号通路（WSP）改变已在前列腺癌患者中被发现，并与疾病进展和激素抵抗有关。在这项研究中，我们利用多机构数据集来描述前列腺癌中经典和非经典 WSP 的分子改变。研究了接受基于组织的基因组测序的前列腺癌患者。具有 CTNNB1 或 RSPO2 体细胞激活突变或 APC 或 RNF43 失活突变的肿瘤被描述为具有异常经典 Wnt 信号（WSP 激活）。总生存分析仅限于缺乏 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 来研究非经典 WSP。在 4138 个前列腺癌样本中，3684 个是 MSS。在 MSS 肿瘤中，42.4%来自转移部位，其中 19.1%为 WSP 激活，57.6%来自前列腺，其中 10.1%为 WSP 激活。WSP 激活的肿瘤在转移部位比在原发性前列腺癌中更为常见。与 WSP-WT 肿瘤相比，WSP 激活的前列腺癌表现出更多的 SPOP 突变和更高的经典 WSP 激活剂表达。ROR1 基因表达在原发和转移部位的 WSP 激活肿瘤中均升高。在 WSP 激活的肿瘤中，M2 巨噬细胞占主导地位。WSP 激活和 WSP-WT 前列腺癌患者的总生存率无显著差异。WSP 激活的前列腺癌表现出更具免疫抑制性的肿瘤微环境和 ROR1 基因表达的显著上调，强调其在经典和非经典 WSP 之间的串扰中可能发挥作用。意义：我们的发现可能为开发针对 Wnt 激活的前列腺癌的新型治疗策略提供依据。
