Summary of project PR002638
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002638. The data can be accessed directly via it's Project DOI: 10.21228/M8NV8F This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002638 |
| Project DOI: | doi: 10.21228/M8NV8F |
| Project Title: | Cell state-driven metabolic dependency in small cell lung cancer |
| Project Type: | Mechanistic Study |
| Project Summary: | Cellular heterogeneity and plasticity are critical traits of tumour evolution and resistance to therapy. Small cell lung cancer (SCLC), a paradigm for the role of tumoral heterogeneity in resistance to therapy, undergoes rampant plasticity between cellular states defined by transcription factors regulating neuroendocrine differentiation. Here, we describe distinct metabolic states associated with neuroendocrine plasticity, revealing key metabolic vulnerabilities underlying cellular states in SCLC. Using integrated transcriptomic and metabolomic approaches, we found that SCLC cells in all states are dependent on exogenous cysteine/cystine (Cys). This dependency is explained by a uniformly low expression of the GNMT enzyme in the cysteine anabolic pathway. Ferroptosis is the most prevalent mechanism of cell death upon Cys deprivation, and SCLC cells in an ASCL1-low state (NEUROD1-high, POU2F3-high, and YAP1-high) died from ferroptosis upon depletion of exogenous Cys; in contrast, cells in the ASCL1-high state were more resistant to ferroptosis and instead underwent late apoptosis. Mechanistically, ASCL1 induces the expression of the GCH1 enzyme, leading to elevated levels of the antioxidant metabolites BH4/BH2, thereby causing ferroptosis resistance. Consequently, inhibition of the BH4/BH2 synthesis pathway sensitizes ASCL1-high SCLC cells to ferroptosis. Accordingly, enzyme-mediated cysteine depletion in combination with inhibition of BH4/BH2 synthesis was effective at reducing tumour growth in patient-derived xenografts (PDXs). Our work identifies distinct metabolic states during SCLC plasticity and demonstrates that Cys dependency is a key metabolic bottleneck that can be exploited for therapeutic strategies in SCLC across various cell death pathways and cell states. |
| Institute: | CECAD Research Center |
| Last Name: | von Karstedt |
| First Name: | Silvia |
| Address: | Joseph-Stelzmann-Straße 26, 50931 Köln |
| Email: | s.vonkarstedt@uni-koeln.de |
| Phone: | +49 221 478 84340 |
Summary of all studies in project PR002638
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST004182 | Metabolomics of ASCL1-high and ASCL1-low SCLC cells in mouse models | Mus musculus | CECAD Research Center | MS | 2025-09-28 | 1 | 20 | Uploaded data (10.1G)* |
| ST004203 | Cell state-specific metabolic networks govern ferroptosis versus apoptosis in small cell lung cancer | Mus musculus | Stanford University | MS | 2025-10-10 | 1 | 6 | Uploaded data (1G)* |
