靶向CERS6-AS1/FGFR1轴作为限制基质细胞的合成脆弱性，支持了地幔细胞淋巴瘤的增殖
Targeting CERS6-AS1/FGFR1 axis as synthetic vulnerability to constrain stromal cells supported proliferation in Mantle cell lymphoma
影响因子:13.40000
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
摘要
肿瘤微环境中基质细胞和肿瘤细胞之间的相互作用是地幔细胞淋巴瘤（MCL）进展和耐药性的关键因素。我们已经确定了在MCL中上调的长无编码RNA CERS6-AS1，并且与总生存期差有关。在基质微环境中，在原代MCL和粘附在基质层的MCL细胞的子集中，CERS6-AS1的表达升高。这些基质粘附的MCL-Subset表现出癌细胞的特征，而不是悬浮液。从机械上讲，我们发现在MCL中下调CERS6-AS1降低了成纤维细胞生长因子受体-1（FGFR1），这是由于其与RNA结合蛋白核素的相互作用丧失所致。此外，使用硅胶方法，我们发现了FGFR1的核苷和5'UTR之间的直接相互作用，从而调节FGFR1转录本稳定性。我们发现CERS6-AS1与癌症干细胞特征和WNT信号传导的正相关。在这些基础上，我们探索了潜在的治疗策略，其中将核糖素靶向剂与FGFR1抑制相结合，显着有助于逆转癌症干细胞的特征并消除基质层上的原发性MCL细胞生长。这些发现为涉及CERS6-AS1，核醇蛋白和FGFR1轴相关的串扰的调节网络提供了机械见解，并在MCL中靶向非编码RNA的治疗潜力。
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.