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间质肿瘤细胞驱动 Trp53 乳腺肿瘤细胞对失活突变 Kras 的适应性抵抗。

Mesenchymal tumor cells drive adaptive resistance of Trp53 breast tumor cells to inactivated mutant Kras.

机构信息

Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, CA, USA.

Department of Stem Cell Biotechnology, California State University Channel Islands, Camarillo, CA, USA.

出版信息

Mol Oncol. 2022 Sep;16(17):3128-3145. doi: 10.1002/1878-0261.13220. Epub 2022 Apr 23.

DOI:10.1002/1878-0261.13220
PMID:35398967
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9441006/
Abstract

As precision medicine increases the response rate of treatment, tumors frequently bypass inhibition, and reoccur. In order for treatment to be effective long term, the mechanisms enabling treatment adaptation need to be understood. Here, we report a mouse model that, in the absence of p53 and the presence of oncogenic Kras , develops breast tumors. Upon inactivation of Kras , tumors initially regress and enter remission. Subsequently, the majority of tumors adapt to the withdrawal of Kras expression and return. Kras -independent tumor cells show a strong mesenchymal profile with active RAS-RAF-MEK-ERK (MAPK/ERK) signaling. Both Kras -dependent and Kras -independent tumors display a high level of genomic instability, and Kras -independent tumors harbor numerous amplified genes that can activate the MAPK/ERK signaling pathway. Our study identifies both epithelial-mesenchymal transition (EMT) and active MAPK/ERK signaling in tumors that adapt to oncogenic Kras withdrawal in a novel Trp53 breast cancer mouse model. To achieve long-lasting responses in the clinic to RAS-fueled cancer, treatment will need to focus in parallel on obstructing tumors from adapting to oncogene inhibition.

摘要

随着精准医学提高了治疗的反应率，肿瘤经常绕过抑制并再次出现。为了使治疗长期有效，需要了解使治疗适应的机制。在这里，我们报告了一个缺乏 p53 和存在致癌性 Kras 的小鼠模型，该模型会发展成乳腺癌。在 Kras 失活后，肿瘤最初会消退并进入缓解期。随后，大多数肿瘤会适应 Kras 表达的撤回并重新出现。Kras 非依赖性肿瘤细胞表现出强烈的间充质特征，具有活跃的 RAS-RAF-MEK-ERK（MAPK/ERK）信号传导。Kras 依赖性和 Kras 非依赖性肿瘤均表现出高水平的基因组不稳定性，并且 Kras 非依赖性肿瘤具有许多可激活 MAPK/ERK 信号通路的扩增基因。我们的研究在一种新型的 Trp53 乳腺癌小鼠模型中，鉴定了适应致癌性 Kras 撤回的肿瘤中的上皮-间充质转化（EMT）和活跃的 MAPK/ERK 信号传导。为了在临床上实现对 RAS 驱动的癌症的持久反应，治疗将需要并行关注阻止肿瘤适应致癌基因抑制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d3cd/9441006/5bdc507cf6da/MOL2-16-3128-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d3cd/9441006/8dd32a198f6a/MOL2-16-3128-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d3cd/9441006/689340f7c367/MOL2-16-3128-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d3cd/9441006/26aab41fbcdc/MOL2-16-3128-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d3cd/9441006/024d5561f0ff/MOL2-16-3128-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d3cd/9441006/5bdc507cf6da/MOL2-16-3128-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d3cd/9441006/8dd32a198f6a/MOL2-16-3128-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d3cd/9441006/689340f7c367/MOL2-16-3128-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d3cd/9441006/26aab41fbcdc/MOL2-16-3128-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d3cd/9441006/024d5561f0ff/MOL2-16-3128-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d3cd/9441006/5bdc507cf6da/MOL2-16-3128-g003.jpg

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Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells.高转移性 Claudin-low 型乳腺癌可起源于腔上皮细胞。
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