Multivalent state transitions shape the intratumoral composition of small cell lung carcinoma
0301 basic medicine
03 medical and health sciences
Lung Neoplasms
Humans
Biomedicine and Life Sciences
Prognosis
Small Cell Lung Carcinoma
DOI:
10.1126/sciadv.abp8674
Publication Date:
2022-12-14T18:58:38Z
AUTHORS (7)
ABSTRACT
Studies to date have not resolved how diverse transcriptional programs contribute to the intratumoral heterogeneity of small cell lung carcinoma (SCLC), an aggressive tumor associated with a dismal prognosis. Here, we identify distinct and commutable transcriptional states that confer discrete functional attributes in individual SCLC tumors. We combine an integrative approach comprising the transcriptomes of 52,975 single cells, high-resolution measurement of cell state dynamics at the single-cell level, and functional and correlative studies using treatment naïve xenografts with associated clinical outcomes. We show that individual SCLC tumors contain distinctive proportions of stable cellular states that are governed by bidirectional cell state transitions. Using drugs that target the epigenome, we reconfigure tumor state composition in part by altering individual state transition rates. Our results reveal new insights into how single-cell transition behaviors promote cell state equilibrium in SCLC and suggest that facile plasticity underlies its resistance to therapy and lethality.
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