Multivalent state transitions shape the intratumoral composition of small cell lung carcinoma
Menée à l'aide de lignées cellulaires, d'un modèle murin et d'échantillons tumoraux issus de patients atteints d'un carcinome du poumon à petites cellules, cette étude identifie des états cellulaires distincts et réversibles qui confèrent hétérogénéité et plasticité à la tumeur
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. Intratumoral diversity in small cell lung cancer is shaped by highly coordinated switches in cellular programs.
Science Advances , article en libre accès, 2021