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

放疗在包括直肠腺癌在内的各种肿瘤的治疗理念中起着不可或缺的作用。对于局部晚期的疾病，标准治疗包括术前放化疗（CRT），然后是根治性手术切除。然而，对CRT的反应是非常不均匀的，从完全反应到完全抵抗。这导致了一个重大的临床困境，因为耐药肿瘤患者受到化疗和放疗潜在的急性和长期副作用的折磨，而没有明显的益处。对于这些患者，肿瘤细胞的（再）致敏将为肿瘤学的基本临床和社会经济问题提供一个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以避免根治性手术切除的发病率和死亡率。在CRT后临床反应完全的情况下，省略手术切除的概念，被称为观察等待策略，目前在该领域讨论颇有争议。由于个体患者对CRT的反应到目前为止是不可预测的，因此迫切需要更个性化的治疗策略。然而，这需要对CRT抗性背后的细胞和分子过程的机制理解，目前这只是零碎的。在过去的资助期内，我们证明了gp130家族的炎症细胞因子受体的刺激和随后的信号换能器和转录激活因子3 （STAT3）的触发赋予CRT对直肠癌细胞的抗性。我们利用这些知识通过阻断STAT3功能使治疗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NOTCH通路的关键转录调控因子RBPJ的表达来实现治疗耐药。此外，术前接受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。总之，我们在过去的资助期内的工作揭示了gp130/STAT3和NOTCH/RBPJ信号之间前所未有的联盟，该联盟驱动CRT抗性。在我们目前工作的直接延续中，我们现在的目标是回答以下问题：(I)四种NOTCH亚型中哪一种通过激活哪种下游效应通路来介导CRT抗性？（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的激活？III)临床能否探索NOTCH通路抑制使癌细胞对CRT再敏感？

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?