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基于CRISPR的分子调控表达平台用于癌症的特异性免疫治疗。

CRISPR-based molecule-regulatory expression platform for specific immunotherapy of cancer.

作者信息

Zhan Tianying, Tong Lu, Wang Linlin, Dong Jun

机构信息

Department of Clinical Laboratory Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.

出版信息

Front Oncol. 2024 Oct 23;14:1469319. doi: 10.3389/fonc.2024.1469319. eCollection 2024.

DOI:10.3389/fonc.2024.1469319
PMID:39507755
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11537849/
Abstract

INTRODUCTION

Cancer is still a major challenge of human health. The abnormality of intracellular cancer-related signal pathways is an important mechanism for the occurrence of cancer.

METHODS

We used a molecular-senor to act on the endogenous signal molecules within the cell to redirect the abnormal signal flows in the cell to treat cancer. Based on CRISPR-dCas12f procedures, we combined aptamers and ribozymes to construct riboswitches, which served as molecular switches to reprogram sgRNAs, so that CRISPR-dCas12f redirected the intracellular anti-cancer signal flows after sensing specific input signal molecules. In addition, the activated molecular sensors and the inhibitory molecular sensors were constructed by combining transcription factors (VP64) and transcription inhibitors (KRAB) to specifically activate and inhibit target genes of interest.

RESULTS

Our experimental results showed that the molecular sensors that we designed and constructed specifically sensed the endogenous signal molecules and then redirect the cancer related signal networks of cancer cells. In addition, corresponding logic gates were constructed to distinguish cancer cells from normal cells and redirect anticancer signal flows to trigger specific cancer immunotherapy.

CONCLUSION

The constructed molecular sensors constructed specifically recognized the signal molecules within the cell and redirected the endogenous signal pathway to reprogram the fate of cancer cells.

摘要

引言

癌症仍然是人类健康的一大挑战。细胞内癌症相关信号通路的异常是癌症发生的重要机制。

方法

我们使用一种分子传感器作用于细胞内的内源性信号分子，以重新引导细胞内的异常信号流来治疗癌症。基于CRISPR-dCas12f程序，我们将适体和核酶结合构建核糖开关，作为分子开关对sgRNAs进行重新编程，从而使CRISPR-dCas在感知特定输入信号分子后重新引导细胞内的抗癌信号流。此外，通过结合转录因子（VP64）和转录抑制剂（KRAB）构建激活型分子传感器和抑制型分子传感器，以特异性激活和抑制感兴趣的靶基因。

结果

我们的实验结果表明，我们设计和构建的分子传感器能够特异性地感知内源性信号分子，然后重新引导癌细胞的癌症相关信号网络。此外，构建了相应的逻辑门以区分癌细胞和正常细胞，并重新引导抗癌信号流以触发特异性癌症免疫疗法。

结论

构建的分子传感器能够特异性识别细胞内的信号分子，并重新引导内源性信号通路以重新编程癌细胞的命运。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b75e/11537849/5015b442230d/fonc-14-1469319-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b75e/11537849/489639bfe051/fonc-14-1469319-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b75e/11537849/4e9e23d1390e/fonc-14-1469319-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b75e/11537849/cc5b4eea97df/fonc-14-1469319-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b75e/11537849/49f0fe6e4262/fonc-14-1469319-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b75e/11537849/5015b442230d/fonc-14-1469319-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b75e/11537849/489639bfe051/fonc-14-1469319-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b75e/11537849/4e9e23d1390e/fonc-14-1469319-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b75e/11537849/cc5b4eea97df/fonc-14-1469319-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b75e/11537849/49f0fe6e4262/fonc-14-1469319-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b75e/11537849/5015b442230d/fonc-14-1469319-g005.jpg

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