靶向CERS6-AS1/FGFR1轴作为合成脆弱性以限制基质细胞支持的弥漫性大B细胞淋巴瘤（MCL）增殖

Targeting CERS6-AS1/FGFR1 axis as synthetic vulnerability to constrain stromal cells supported proliferation in Mantle cell lymphoma

LEUKEMIA

影响因子:13.4

分区:医学1区 Top / 血液学1区肿瘤学2区

发表日期:2024 Oct

作者: Udita Jindal, Mukesh Mamgain, Uttam Kumar Nath, Isha Sharma, Bhaskar Pant, Ankita Sharma, Archita Gupta, Khaliqur Rahman, Sunil Yadav, Manish Pratap Singh, Shaktiprasad Mishra, Chandra Praksah Chaturvedi, Jose Courty, Navin Singh, Seema Gupta, Sanjeev Kumar, Shailendra Prasad Verma, Saumyaranjan Mallick, Ajay Gogia, Sunil Raghav, Jayanta Sarkar, Kinshuk Raj Srivastava, Dipak Datta, Neeraj Jain

DOI: 10.1038/s41375-024-02344-1

摘要

基质细胞与肿瘤细胞在肿瘤微环境中的相互作用是弥漫性大B细胞淋巴瘤（MCL）进展和耐药的重要因素。我们鉴定出一条长链非编码RNA，CERS6-AS1，在MCL中上调并与总体生存率较差相关。CERS6-AS1在原发性MCL以及与基质层粘附的MCL细胞子集中的表达升高。这些粘附于基质的MCL亚群表现出比悬浮细胞更强的癌症干细胞标志。机制上，我们发现抑制CERS6-AS1会降低成纤维细胞生长因子受体-1（FGFR1）的表达，归因于其与RNA结合蛋白核糖素（nucleolin）相互作用的丧失。此外，利用体外分析方法，我们发现核糖素与FGFR1的5'UTR存在直接相互作用，从而调节FGFR1转录本的稳定性。我们还发现CERS6-AS1与癌症干细胞标志和Wnt信号通路呈正相关。在此基础上，我们探索了潜在的治疗策略，即结合核糖素靶向药物与FGFR1抑制剂，显著逆转癌症干细胞标志并抑制MCL在基质层的生长。这些研究提供了涉及CERS6-AS1、核糖素和FGFR1轴的调控网络的机制性见解，并突出了靶向非编码RNA在MCL治疗中的潜在应用前景。

Abstract

The interaction between stromal and tumor cells in tumor microenvironment is a crucial factor in Mantle cell lymphoma (MCL) progression and therapy resistance. We have identified a long non-coding RNA, CERS6-AS1, upregulated in MCL and associated with poor overall survival. CERS6-AS1 expression was elevated in primary MCL within stromal microenvironment and in a subset of MCL cells adhered to stromal layer. These stromal-adhered MCL-subsets exhibited cancer stem cell signatures than suspension counterparts. Mechanistically, we found that downregulating CERS6-AS1 in MCL reduced Fibroblast Growth Factor Receptor-1 (FGFR1), expression attributed to loss of its interaction with RNA-binding protein nucleolin. In addition, using in-silico approach, we have discovered a direct interaction between nucleolin and 5'UTR of FGFR1, thereby regulating FGFR1 transcript stability. We discovered a positive association of CERS6-AS1 with cancer stem cell signatures, and Wnt signaling. Building on these, we explored potential therapeutic strategies where combining nucleolin-targeting agent with FGFR1 inhibition significantly contributed to reversing cancer stem cell signatures and abrogated primary MCL cell growth on stromal layer. These findings provide mechanistic insights into regulatory network involving CERS6-AS1, nucleolin, and FGFR1 axis-associated crosstalk between tumor cells and stromal cell interaction and highlights therapeutic potential of targeting a non-coding RNA in MCL.