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

• Published in: Leukemia 2024-10, Vol.38 (10), p.2196-2209
• Main Authors: Jindal, Udita, Mamgain, Mukesh, Nath, Uttam Kumar, Sharma, Isha, Pant, Bhaskar, Sharma, Ankita, Gupta, Archita, Rahman, Khaliqur, Yadav, Sunil, Singh, Manish Pratap, Mishra, Shaktiprasad, Chaturvedi, Chandra Praksah, Courty, Jose, Singh, Navin, Gupta, Seema, Kumar, Sanjeev, Verma, Shailendra Prasad, Mallick, Saumyaranjan, Gogia, Ajay, Raghav, Sunil, Sarkar, Jayanta, Srivastava, Kinshuk Raj, Datta, Dipak, Jain, Neeraj
• Format: Article
• Language: English
• Subjects: 13/106; 13/2; 13/31; 13/89; 38/39; 38/44; 5' Untranslated Regions; 631/67/327; 692/699/67/71; 82/1; 82/29; 82/80; 96/100; Cancer; Cancer Research; Cell proliferation; Critical Care Medicine; Fibroblast growth factor receptor 1; Gene expression; Growth factors; Hematology; Intensive; Internal Medicine; Lymphoma; Mantle cell lymphoma; Medicine; Medicine & Public Health; Non-coding RNA; Nucleolin; Oncology; Pharmacology; RNA-binding protein; Signatures; Stem cells; Stromal cells; Tumor cells; Tumor microenvironment; Tumors; Wnt protein
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-024-02344-1

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.