The role of NOTCH signaling in mediating rectal cancer resistance to chemoradiotherapy

NOTCH信号在介导直肠癌放化疗耐药中的作用

• 批准号: 288437061
• 负责人: Privatdozent Dr. Marian Grade
• 金额: --
• 依托单位: Institut für Zelluläre und Molekulare Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/288437061?language=en
• 关键词: role; NOTCH; signaling; mediating; rectal

Radiotherapy plays an integral part in treatment concepts for various tumor entities, including adenocarcinomas of the rectum. For locally advanced stages of this disease, the standard treatment involves preoperative chemoradiotherapy (CRT), followed by radical surgical resection. However, the response to CRT is very heterogenous, and ranges from complete response to complete resistance. This leads to a significant clinical dilemma, because patients with resistant tumors are afflicted with the potential acute and long-term side effects of both chemotherapy and radiation without a clear benefit. For these patients, (re-) sensitization of tumor cells would offer an attractive solution to a fundamental clinical and socioeconomic problem in oncology. On the other hand, patients with a complete tumor response after preoperative treatment may be spared from the morbidity and mortality of radical surgical resection. The concept to omit surgical resection in case of a complete clinical response after CRT, which is referred to as watch-and-wait strategy, is currently controversially discussed in the field. Because the individual patient’s responsiveness to CRT is so far unpredictable, more personalized treatment strategies are urgently needed. This, however, requires a mechanistic understanding of the cellular and molecular processes underlying CRT resistance, which is currently only fragmentary. During the past funding period, we demonstrated that the stimulation of inflammatory cytokine receptors of the gp130 family and the subsequent triggering of Signal Transducer and Activator of Transcription 3 (STAT3) conferred CRT resistance to rectal cancer cells. We used that knowledge to re-sensitize treatment-refractory cancer cells by blocking STAT3 function, and moreover, abolished the growth of STAT3-inhibited tumors in a xenograft mouse model. We also deciphered the mode-of-action of STAT3-mediated CRT unresponsiveness. STAT3 executed treatment resistance by triggering the expression of RBPJ, the key transcriptional regulator of the NOTCH pathway. Moreover, NOTCH receptor expression in pretherapeutic biopsies from patients treated with preoperative CRT correlated with clinical outcome. Altogether, our work of the past funding period uncovered an unprecedented alliance between gp130/STAT3 and NOTCH/RBPJ signaling that drives CRT resistance. In direct continuation of our work so far, we now aim at answering the following questions: (I) Which of the four NOTCH isoforms mediates CRT resistance by activating what kind of downstream effector pathway? (II) What is the role of the tumor microenvironment and does it contribute to NOTCH activation by providing the necessary ligands? III) Can NOTCH pathway inhibition be explored clinically to re-sensitize cancer cells to CRT?

放射治疗在包括直肠腺癌在内的各种肿瘤的治疗概念中发挥着不可或缺的作用。对于这种疾病的局部晚期阶段，标准治疗包括术前放化疗（CRT），然后进行根治性手术切除。然而，对 CRT 的反应非常不同，从完全反应到完全抵抗。这导致了一个重大的临床困境，因为耐药肿瘤患者遭受化疗和放疗潜在的急性和长期副作用的困扰，而没有明显的益处。对于这些患者来说，肿瘤细胞的（重新）致敏将为肿瘤学中的基本临床和社会经济问题提供有吸引力的解决方案。另一方面，术前治疗后肿瘤完全缓解的患者可能会避免根治性手术切除的发病率和死亡率。如果 CRT 后出现完全临床反应，则省略手术切除的概念（称为观察等待策略）目前在该领域存在争议。由于迄今为止个体患者对 CRT 的反应是不可预测的，因此迫切需要更个性化的治疗策略。然而，这需要对 CRT 耐药性背后的细胞和分子过程有一个机械的理解，而目前这只是零碎的理解。在过去的资助期间，我们证明了 gp130 家族炎症细胞因子受体的刺激以及随后信号转导器和转录激活剂 3 (STAT3) 的触发赋予了直肠癌细胞 CRT 抵抗性。我们利用这些知识通过阻断 STAT3 功能来使难治性癌细胞重新敏感，此外，在异种移植小鼠模型中消除了 STAT3 抑制的肿瘤的生长。我们还破译了 STAT3 介导的 CRT 无反应的作用模式。 STAT3通过触发RBPJ（NOTCH通路的关键转录调节因子）的表达来执行治疗抵抗。此外，接受术前 CRT 治疗的患者的治疗前活检中 NOTCH 受体的表达与临床结果相关。总而言之，我们在过去的资助期间的工作发现了 gp130/STAT3 和 NOTCH/RBPJ 信号之间前所未有的联盟，从而驱动了 CRT 耐药性。在迄今为止我们工作的直接延续中，我们现在的目标是回答以下问题：（I）四种 NOTCH 亚型中的哪一种通过激活哪种下游效应通路来介导 CRT 耐药？ (II) 肿瘤微环境的作用是什么？它是否通过提供必要的配体来促进NOTCH激活？ III) 能否在临床上探索 NOTCH 通路抑制，使癌细胞对 CRT 重新敏感？