Wiley Mark B, Bauer Jessica, Alvarez Valentina, Kolics Zoe, Cheng Wenxuan, Church David N, Kerr David J, Kerr Rachel S, Jung Barbara
Department of Medicine, University of Washington College of Medicine, Seattle, WA, 98195, USA.
Nuffield Department of Medicine, University of Oxford, Oxford, OX1 4BH, UK.
Sci Rep. 2025 Mar 12;15(1):8509. doi: 10.1038/s41598-025-91853-9.
Advanced colorectal cancer (CRC) continues to present with poor survival and treatment options remain limited. We have shown that increased activin A (activin) expression in the tumor microenvironment (TME) is associated with poor outcome in a cohort of stage III and IV CRC patients. Here, we hypothesized that activin promotes stage specific outcomes in CRC, enhancing metastasis and tolerance in late-stage CRC exclusively. We employed Digital Spatial Profiling (DSP) technology on a cohort of stage II and III CRC patient tissue samples obtained at the time of curative surgery to show that activin co-localization was associated with increased mitogenic signaling, proliferation, and immunosuppression in stage III, but not stage II, CRCs. Furthermore, we found strong linear correlations between markers of immunosuppression and signaling proteins in activin (+) areas, an effect that was not observed in activin (-) areas of tissue. Taken together these data suggest activin exerts pro-metastatic and immunosuppressive effects in stage III, but not stage II, CRC providing an attractive therapeutic target for advanced CRC.
晚期结直肠癌（CRC）的生存率仍然很低，治疗选择也很有限。我们已经表明，肿瘤微环境（TME）中激活素A（激活素）表达的增加与一组III期和IV期CRC患者的不良预后相关。在此，我们假设激活素促进CRC的阶段特异性结果，仅在晚期CRC中增强转移和耐受性。我们对一组在根治性手术时获得的II期和III期CRC患者组织样本采用数字空间分析（DSP）技术，以表明激活素共定位与III期而非II期CRC中的促有丝分裂信号传导、增殖和免疫抑制增加相关。此外，我们发现免疫抑制标志物与激活素（+）区域中的信号蛋白之间存在强线性相关性，而在组织的激活素（-）区域中未观察到这种效应。综合这些数据表明，激活素在III期而非II期CRC中发挥促转移和免疫抑制作用，为晚期CRC提供了一个有吸引力的治疗靶点。
