image: (A) SRAMP analysis of the secondary structure of ROLLCSC and its potential m6A methylation sites. (B) Venn diagram showing methylation-related proteins specifically interacting with the sense strand. (C and D) RIP assay validating the interaction between ROLLCSC and the target protein, with IgG as a negative control. (E) Western blot confirming the specific interaction between ROLLCSC and the target protein. (F) Regulation of ROLLCSC expression by FTO inhibitor. (G) Effect of FTO inhibitor on the stability of the ROLLCSC gene, with ActD concentration at 2 μM. (H) MeRIP analysis of the impact of FTO inhibitor on the m6A methylation level of ROLLCSC. (I) Efficiency of lentiviral overexpression of FTO. (J) Regulation of ROLLCSC expression by lentiviral overexpression of FTO. (K) Effect of lentiviral FTO overexpression on the stability of the ROLLCSC gene, with ActD concentration at 2 μM. (L) MeRIP analysis of the impact of FTO inhibitor on the m6A methylation level of ROLLCSC. (M) Knockdown efficiency of si-Igf2bp2. (N) PCR analysis of the effect of si-Igf2bp2 on ROLLCSC expression. (O) Effect of si-Igf2bp2 on the stability of the ROLLCSC gene, with ActD concentration at 2 μM. (P–Q) Representative images and statistical analysis of transwell assay results for each group. Six randomly selected images per group were used for data analysis. (∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001. ns, not significant. The results represent three independent experiments.)
Credit: Yu-Han Zhang, Jia-Cheng Xie, Ting Ye, Shi-Meng Guo, Xue Han, Si Yang, Lei Shi, Yi-Shi Li, H. Rosie Xing, Jing-Yu Li, Jian-Yu Wang
This new research, published in the Genes & Diseases journal by a team from Chongqing Medical University and Southwest Medical University, investigated the precise mechanisms by which the long non-coding RNA (lncRNA) ROLLCSC transfers metastatic capacity from LUAD stem cells to non-stem cells.
Through extensive molecular experiments and multi-omics analyses, the researchers discovered a highly intricate positive feedback loop driving EV uptake. They demonstrated that the GTPase protein CDC42 facilitates the encapsulation of ROLLCSC into LUAD stem cell-derived EVs. Once internalized by recipient lung cancer cells, ROLLCSC is stabilized through FTO-mediated m6A demethylation and subsequently recognized by the reader protein IGF2BP2. This enhanced stability allows ROLLCSC to profoundly reshape the cellular lipid metabolism of the recipient cells.
Specifically, ROLLCSC acts as a scaffold to facilitate the interaction between the E3 ubiquitin ligase ELOC and ACSL4, thereby accelerating the degradation of ACSL4. Since ACSL4 is a critical promoter of lipid peroxidation, its degradation significantly suppresses cellular susceptibility to ferroptosis. Furthermore, ROLLCSC functions as a competing endogenous RNA (ceRNA) targeting miR-5623-3p to upregulate SLC25A11, which improves intra-mitochondrial glutathione (GSH) transport to further counteract oxidative stress.
Remarkably, in vivo orthotopic lung metastasis models confirmed that inhibiting this ROLLCSC-mediated signaling axis—such as through ACSL4 overexpression or ELOC knockdown—significantly restored ferroptosis sensitivity and sharply reduced metastatic tumor foci in the lungs. Clinical data corroborated these findings, revealing that elevated ROLLCSC, CDC42, and SLC25A11 expression levels strongly correlate with advanced tumor progression and poor overall survival in LUAD patients.
While these collective data robustly highlight the critical influence of EV-mediated lipid metabolic reprogramming in driving tumor aggressiveness, additional studies are necessary to confirm the efficacy of ROLLCSC-targeted therapies in broader clinical settings.
In conclusion, disrupting the EV-delivered ROLLCSC signaling network offers a dual-action strategy, simultaneously enhancing ferroptosis and inhibiting metabolic-driven metastasis. This profound finding positions specific inhibitors of ROLLCSC and its downstream metabolic targets as compelling candidates for next-generation lung adenocarcinoma therapies.
Reference
Title of Original Paper: Intratumoral microenvironment remodeling by lncRNA ROLLCSC enhances lung adenocarcinoma progression
Journal: Genes & Diseases
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