A non-genetic, cell cycle-dependent mechanism of platinum resistance in lung adenocarcinoma.
Alvaro Gonzalez RajalKamila A MarzecRachael A McCloyMax NobisVenessa ChinJordan F HastingsKaitao LaiMarina L KennersonWilliam E HughesVijesh VaghjianiPaul TimpsonJason E CainD Neil WatkinsDavid R CroucherAndrew BurgessPublished in: eLife (2021)
We previously used a pulse-based in vitro assay to unveil targetable signalling pathways associated with innate cisplatin resistance in lung adenocarcinoma (Hastings et al., 2020). Here, we advanced this model system and identified a non-genetic mechanism of resistance that drives recovery and regrowth in a subset of cells. Using RNAseq and a suite of biosensors to track single-cell fates both in vitro and in vivo, we identified that early S phase cells have a greater ability to maintain proliferative capacity, which correlated with reduced DNA damage over multiple generations. In contrast, cells in G1, late S or those treated with PARP/RAD51 inhibitors, maintained higher levels of DNA damage and underwent prolonged S/G2 phase arrest and senescence. Combined with our previous work, these data indicate that there is a non-genetic mechanism of resistance in human lung adenocarcinoma that is dependent on the cell cycle stage at the time of cisplatin exposure.
Keyphrases
- cell cycle
- dna damage
- induced apoptosis
- cell proliferation
- cell cycle arrest
- dna repair
- oxidative stress
- endothelial cells
- single cell
- immune response
- genome wide
- magnetic resonance
- magnetic resonance imaging
- high throughput
- copy number
- computed tomography
- gene expression
- electronic health record
- machine learning
- cell death
- rna seq
- deep learning
- induced pluripotent stem cells
- label free