EMBO Mol Med.: LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma

LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma

Our most recent collaborative study with several partners from the SPP 2306

Conrad M, Schulze A, Trumpp A, Friedmann Angeli JP

Alborizina et al 2023

Schematic representation for the proposed model of LRP8 inhibition essentiality. Comparison of selenium /selenocysteine uptake mechanisms via LRP8 and system Xc in proliferating MYCN- amplified cells, depicting the contribution of primarily LRP8/SELENOP supporting selenoprotein translation (left panel). Inhibition of LRP8 in system Xc low cell selectively triggers ferroptosis in MYCN-amplified neuroblastoma (right panel). SELENOP, Selenoprotein P; iSe, inorganic selenium; SeCys, Selenocysteine.

(Figure adopted from Alborzinia H et al., 2023 PMID: 37435859).

Ferroptosis has emerged as an attractive strategy in cancer therapy. Understanding the operational networks regulating ferroptosis may unravel vulnerabilities that could be harnessed for therapeutic benefit. Using CRISPR-activation screens in ferroptosis hypersensitive cells, we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis. Genetic deletion of LRP8 leads to ferroptosis as a result of an insufficient supply of selenocysteine, which is required for the translation of the antiferroptotic selenoprotein GPX4. This dependency is caused by low expression of alternative selenium uptake pathways such as system Xc^– . The identification of LRP8 as a specific vulnerability of MYCN-amplified neuroblastoma cells was confirmed in constitutive and inducible LRP8 knockout orthotopic xenografts. These findings disclose a yet-unaccounted mechanism of selective ferroptosis induction that might be explored as a therapeutic strategy for high-risk neuroblastoma and potentially other MYCN-amplified entities.

Original publication:

LRP8-mediated selenocysteine uptake is a targetable vulnerability in MYCN-amplified neuroblastoma.

Alborzinia H, Chen Z, Yildiz U, Freitas FP, Vogel FCE, Varga JP, Batani J, Bartenhagen C, Schmitz W, Büchel G, Michalke B, Zheng J, Meierjohann S, Girardi E, Espinet E, Flórez AF, Dos Santos AF, Aroua N, Cheytan T, Haenlin J, Schlicker L, Xavier da Silva TN, Przybylla A, Zeisberger P, Superti-Furga G, Eilers M, Conrad M, Fabiano M, Schweizer U, Fischer M, Schulze A, Trumpp A, Friedmann Angeli JP.

EMBO Mol Med. 2023 Jul 12:e18014. doi: 10.15252/emmm.202318014. Online ahead of print. PMID: 37435859 Free article.

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