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一种细胞命运重编程策略可逆转肺癌细胞的上皮-间充质转化，同时避免杂交状态。

A Cell-Fate Reprogramming Strategy Reverses Epithelial-to-Mesenchymal Transition of Lung Cancer Cells While Avoiding Hybrid States.

机构信息

Laboratory for Systems Biology and Bio-inspired Engineering, Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.

Aventi Inc., Daejeon, Republic of Korea.

出版信息

Cancer Res. 2023 Mar 15;83(6):956-970. doi: 10.1158/0008-5472.CAN-22-1559.

DOI:10.1158/0008-5472.CAN-22-1559
PMID:36710400
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10015224/
Abstract

UNLABELLED

The epithelial-to-mesenchymal transition (EMT) of primary cancer contributes to the acquisition of lethal properties, including metastasis and drug resistance. Blocking or reversing EMT could be an effective strategy to improve cancer treatment. However, it is still unclear how to achieve complete EMT reversal (rEMT), as cancer cells often transition to hybrid EMT states with high metastatic potential. To tackle this problem, we employed a systems biology approach and identified a core-regulatory circuit that plays the primary role in driving rEMT without hybrid properties. Perturbation of any single node was not sufficient to completely revert EMT. Inhibition of both SMAD4 and ERK signaling along with p53 activation could induce rEMT in cancer cells even with TGFβ stimulation, a primary inducer of EMT. Induction of rEMT in lung cancer cells with the triple combination approach restored chemosensitivity. This cell-fate reprogramming strategy based on attractor landscapes revealed potential therapeutic targets that can eradicate metastatic potential by subverting EMT while avoiding hybrid states.

SIGNIFICANCE

Network modeling unravels the highly complex and plastic process regulating epithelial and mesenchymal states in cancer cells and discovers therapeutic interventions for reversing epithelial-to-mesenchymal transition and enhancing chemosensitivity.

摘要

未加标签

原发性癌症的上皮-间质转化 (EMT) 有助于获得致命特性，包括转移和耐药性。阻断或逆转 EMT 可能是改善癌症治疗的有效策略。然而，如何实现完全的 EMT 逆转 (rEMT) 仍不清楚，因为癌细胞通常会过渡到具有高转移潜力的混合 EMT 状态。为了解决这个问题，我们采用了系统生物学方法，鉴定了一个核心调控回路，该回路在驱动 rEMT 而不具有混合特性方面发挥主要作用。扰动任何单个节点都不足以完全逆转 EMT。抑制 SMAD4 和 ERK 信号以及激活 p53 可以诱导即使在 TGFβ刺激下也具有 EMT 主要诱导剂的癌细胞发生 rEMT。用三组合方法诱导肺癌细胞发生 rEMT 可恢复化疗敏感性。基于吸引子景观的这种细胞命运重编程策略揭示了潜在的治疗靶点，这些靶点可以通过颠覆 EMT 来消除转移潜力，同时避免混合状态。

意义

网络建模揭示了调节癌细胞中上皮和间充质状态的高度复杂和可塑性过程，并发现了用于逆转上皮-间质转化和增强化疗敏感性的治疗干预措施。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/1e5fc70b8519/956fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/a76af318920e/overview_graphic_can-22-1559.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/ac6be4612e08/956fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/970d8dea4f09/956fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/5a2da4473536/956fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/fd7da25343e9/956fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/10de47d9b2b4/956fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/73e944ddff7b/956fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/1e5fc70b8519/956fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/a76af318920e/overview_graphic_can-22-1559.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/ac6be4612e08/956fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/970d8dea4f09/956fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/5a2da4473536/956fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/fd7da25343e9/956fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/10de47d9b2b4/956fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/73e944ddff7b/956fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/82c2/10015224/1e5fc70b8519/956fig7.jpg

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