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鉴定MRTFA/SRF信号通路是癌症中静止状态的关键调节因子。

Identification of the MRTFA/SRF pathway as a critical regulator of quiescence in cancer.

作者信息

Panesso-Gómez Santiago, Cole Alexander J, Wield Alyssa, Anyaeche Vivian I, Shah Jaynish, Jiang Qi, Ebai Tonge, Sharrow Allison C, Tseng George, Yoon Euisik, Brown Daniel D, Clark Amanda M, Larsen Scott D, Eder Ian, Gau David, Roy Partha, Dahl Kris N, Tran Lam, Jiang Hui, McAuliffe Priscilla F, Lee Adrian V, Buckanovich Ronald J

机构信息

Department of Internal Medicine and Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, PA, USA.

Australian Centre for Blood Diseases, Central Clinical School, Monash University and Alfred Health, Melbourne, VIC, Australia.

出版信息

bioRxiv. 2024 Nov 17:2024.11.15.623825. doi: 10.1101/2024.11.15.623825.

DOI:10.1101/2024.11.15.623825
PMID:39605642
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11601311/
Abstract

Chemoresistance is a major driver of cancer deaths. One understudied mechanism of chemoresistance is quiescence. We used single cell culture to identify, retrieve, and RNA-Seq profile primary quiescent ovarian cancer cells (qOvCa). We found that many qOvCa differentially expressed genes are transcriptional targets of the Myocardin Related Transcription Factor/Serum Response Factor (MRTF/SRF) pathway. We also found that genetic disruption of MRTF-SRF interaction, or an MRTF/SRF inhibitor (CCG257081) impact qOvCa gene expression and induce a quiescent state in cancer cells. Suggesting a broad role for this pathway in quiescence, CCG257081 treatment induced quiescence in breast, lung, colon, pancreatic and ovarian cancer cells. Furthermore, CCG081 (i) maintained a quiescent state in patient derived breast cancer organoids and, (ii) induced tumor growth arrest in ovarian cancer xenografts. Together, these data suggest that MRTF/SRF pathway is a critical regulator of quiescence in cancer and a possible therapeutic target.

摘要

化疗耐药是癌症死亡的主要驱动因素。一种尚未得到充分研究的化疗耐药机制是细胞静止。我们使用单细胞培养来鉴定、获取原发性静止性卵巢癌细胞（qOvCa）并对其进行RNA测序分析。我们发现，许多qOvCa差异表达基因是心肌素相关转录因子/血清反应因子（MRTF/SRF）信号通路的转录靶点。我们还发现，MRTF-SRF相互作用的基因破坏或MRTF/SRF抑制剂（CCG257081）会影响qOvCa基因表达，并在癌细胞中诱导静止状态。CCG257081处理可在乳腺癌、肺癌、结肠癌、胰腺癌和卵巢癌细胞中诱导静止，这表明该信号通路在静止中发挥广泛作用。此外，CCG081（i）在患者来源的乳腺癌类器官中维持静止状态，（ii）在卵巢癌异种移植物中诱导肿瘤生长停滞。总之，这些数据表明MRTF/SRF信号通路是癌症静止的关键调节因子，也是一个可能的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/2151b075a670/nihpp-2024.11.15.623825v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/21c8a5888ddd/nihpp-2024.11.15.623825v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/b7b20cfe588b/nihpp-2024.11.15.623825v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/9aeafd1aabfb/nihpp-2024.11.15.623825v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/bcbf1f145f93/nihpp-2024.11.15.623825v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/fa0acdc397e0/nihpp-2024.11.15.623825v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/671bd7d63223/nihpp-2024.11.15.623825v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/2151b075a670/nihpp-2024.11.15.623825v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/21c8a5888ddd/nihpp-2024.11.15.623825v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/b7b20cfe588b/nihpp-2024.11.15.623825v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/9aeafd1aabfb/nihpp-2024.11.15.623825v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/bcbf1f145f93/nihpp-2024.11.15.623825v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/fa0acdc397e0/nihpp-2024.11.15.623825v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/671bd7d63223/nihpp-2024.11.15.623825v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0969/11601311/2151b075a670/nihpp-2024.11.15.623825v1-f0007.jpg

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