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Emergence of a High-Plasticity Cell State during Lung Cancer Evolution.

ABSTRACT: Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS.

SUBMITTER: Marjanovic ND 

PROVIDER: S-EPMC7745838 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Emergence of a High-Plasticity Cell State during Lung Cancer Evolution.

Marjanovic Nemanja Despot ND   Hofree Matan M   Chan Jason E JE   Canner David D   Wu Katherine K   Trakala Marianna M   Hartmann Griffin G GG   Smith Olivia C OC   Kim Jonathan Y JY   Evans Kelly Victoria KV   Hudson Anna A   Ashenberg Orr O   Porter Caroline B M CBM   Bejnood Alborz A   Subramanian Ayshwarya A   Pitter Kenneth K   Yan Yan Y   Delorey Toni T   Phillips Devan R DR   Shah Nisargbhai N   Chaudhary Ojasvi O   Tsankov Alexander A   Hollmann Travis T   Rekhtman Natasha N   Massion Pierre P PP   Poirier John T JT   Mazutis Linas L   Li Ruifang R   Lee Joo-Hyeon JH   Amon Angelika A   Rudin Charles M CM   Jacks Tyler T   Regev Aviv A   Tammela Tuomas T  

Cancer cell 20200723 2

Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high  ...[more]

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