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

Autor: Jindal U; Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, 226031, India.; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India., Mamgain M; Department of Medical Oncology & Hematology, All India Institute of Medical Sciences, Rishikesh, 249203, India., Nath UK; Department of Medical Oncology & Hematology, All India Institute of Medical Sciences, Rishikesh, 249203, India., Sharma I; Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, 226031, India., Pant B; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India.; Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, 226031, India., Sharma A; Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, 226031, India., Gupta A; Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, 226031, India., Rahman K; Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India., Yadav S; Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India., Singh MP; Department of Zoology, Deen Dayal Upadhyay Gorakhpur University, Gorakhpur, Uttar Pradesh, 273009, India., Mishra S; Institute of Life Sciences, Bhubaneswar, 751023, Odisha, India., Chaturvedi CP; Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, 226014, India., Courty J; INSERM, Institut Mondor de Recherche Biomédicale (IMRB), Université Paris-Est Créteil, F-94010, Créteil, France., Singh N; Department of Radiotherapy, King George's Medical University, Lucknow, Uttar Pradesh, 226003, India., Gupta S; Department of Radiotherapy, King George's Medical University, Lucknow, Uttar Pradesh, 226003, India., Kumar S; Department of General Surgery, King George's Medical University, Lucknow, Uttar Pradesh, 226003, India., Verma SP; Department of Clinical Hematology, King George's Medical University, Lucknow, Uttar Pradesh, 226003, India., Mallick S; Department of Pathology, All India Institute of Medical Sciences, New Delhi, 110029, India., Gogia A; Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, 110029, India., Raghav S; Institute of Life Sciences, Bhubaneswar, 751023, Odisha, India., Sarkar J; Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, 226031, India.; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India., Srivastava KR; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India.; Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, 226031, India., Datta D; Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, 226031, India.; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India., Jain N; Division of Cancer Biology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, 226031, India. neeraj.jainfellow@cdri.res.in.; Academy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh, 201002, India. neeraj.jainfellow@cdri.res.in.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2024 Oct; Vol. 38 (10), pp. 2196-2209. Date of Electronic Publication: 2024 Jul 13.
DOI: 10.1038/s41375-024-02344-1
Abstrakt: 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.
(© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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