Sanchis Pablo, Sabater Agustina, Lechuga Julia, Rada Jimena, Seniuk Rocio, Pascual Gaston, Gatti Mora, Bizzotto Juan, Shepherd Peter D A, Yang Jun, Cotignola Javier, Vazquez Elba, Mateo Joaquin, Valacco Pia, Labanca Estefania, Logothetis Christopher, Gueron Geraldine, Anselmino Nicolas
Department of Genitourinary Medical Oncology and The David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Laboratorio de Inflamación y Cáncer, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
Oncogene. 2025 Aug 2. doi: 10.1038/s41388-025-03511-z.
Prostate cancer (PCa) bone metastasis (BM) poses a significant clinical challenge due to the heterogeneity of treatment responses and patient outcomes. In this study, we examined the role of Protein Kinase A (PKA) signaling in modulating the expression of osteopontin (SPP1/OPN), a protein associated with poor prognosis, within a subset of PCa BM patients. By integrating multi-omics results we identified a novel mechanism in which bone-derived type-I collagen (Col1a1) and fibronectin (Fn1) stimulate SPP1 expression in PCa cells through the activation of PKA signaling. This bone-induced regulation of SPP1 was confirmed both in vitro, using PCa-bone co-culture systems (PC3 or C42B/MC3T3 cell lines), and in vivo, using cell lines' engraftments and patient-derived xenografts (PDX) grown intrafemorally. Importantly, clinical data from longitudinal patient samples revealed that treatment with enzalutamide, an androgen receptor (AR) inhibitor, led to an increase in PKA signaling and corresponding SPP1 expression in a subpopulation of patients, highlighting the relevance of the PKA/SPP1 axis in disease progression under AR-targeted therapies. Overall, we underscored the critical role of the bone microenvironment in influencing PCa progression, pointing out to SPP1/OPN as a biomarker for identifying tumors with active PKA signaling, which could serve to manage resistance to AR-directed treatments.
前列腺癌（PCa）骨转移（BM）由于治疗反应和患者预后的异质性而带来了重大的临床挑战。在本研究中，我们在一部分PCa BM患者中研究了蛋白激酶A（PKA）信号传导在调节骨桥蛋白（SPP1/OPN）表达中的作用，骨桥蛋白是一种与预后不良相关的蛋白质。通过整合多组学结果，我们发现了一种新机制，即骨源性I型胶原蛋白（Col1a1）和纤连蛋白（Fn1）通过激活PKA信号传导来刺激PCa细胞中SPP1的表达。这种由骨诱导的SPP1调节在体外使用PCa-骨共培养系统（PC3或C42B/MC3T3细胞系）以及在体内使用细胞系植入物和股内生长的患者来源异种移植（PDX）均得到了证实。重要的是，来自纵向患者样本的临床数据显示，使用雄激素受体（AR）抑制剂恩杂鲁胺治疗导致一部分患者的PKA信号传导和相应的SPP1表达增加，突出了PKA/SPP1轴在AR靶向治疗下疾病进展中的相关性。总体而言，我们强调了骨微环境在影响PCa进展中的关键作用，指出SPP1/OPN作为识别具有活跃PKA信号传导肿瘤的生物标志物，可用于管理对AR导向治疗的耐药性。
