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

Marjanovic, Nemanja D.; Hofree, Matan; Chan, Jason E.; Canner, David; Wu, Katherine; Trakala, Marianna; Hartmann, G. C.; Smith, Olivia; Kim, Jonathan Y.; Evans, Kelly V.; Hudson, Anna; Ashenberg, Orr; Porter, Caroline; Bejnood, Alborz; Subramanian, Ayshwarya; Pitter, Kenneth L.; Yan, Yan; Delorey, Toni; Phillips, Devan; Shah, Nisargbhai; Chaudhary, Ojasvi; Tsankov, Alexander M.; Hollmann, Travis J.; Rekhtman, Natasha; Massion, Pierre P.; Poirier, John T.; Mažutis, Linas; Li, Ruifang; Lee, Joo Hyeon; Amon, Angelika; Rudin, Charles M.; Jacks, Tyler; Regev, Aviv; Tammela, Tuomas

doi:10.1016/j.ccell.2020.06.012

Cited by 268 publications

(337 citation statements)

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“…While plasticity has been discussed in the context of differentiation 89,[119][120][121][122][123][124][125][126][127] and cancer 17,[21][22][23]25,47,71,120,123,[128][129][130][131][132][133][134] many times, it has not been rigorously quantified for individual cells. In quantifying plasticity, we wanted to capture the local likelihood of phenotypic transition (that is, change in gene expression profile) for each transcriptional state sampled.…”

Section: Cell Transport Potential Calculation and Analysismentioning

confidence: 99%

Cancer Hallmarks Define a Continuum of Plastic Cell States between Small Cell Lung Cancer Archetypes

Ireland

et al. 2021

Preprint

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Small Cell Lung Cancer (SCLC) tumors are heterogeneous mixtures of transcriptional subtypes. Understanding subtype dynamics could be key to explaining the aggressive properties that make SCLC a recalcitrant cancer. Applying archetype analysis and evolutionary theory to bulk and single-cell transcriptomics, we show that SCLC cells reside within a cell-state continuum rather than in discrete subtype clusters. Gene expression signatures and ontologies indicate each vertex of the continuum corresponds to a functional phenotype optimized for a cancer hallmark task: three neuroendocrine archetypes specialize in proliferation/survival, inflammation and immune evasion, and two non-neuroendocrine archetypes in angiogenesis and metabolic dysregulation. Single cells can trade-off between these defined tasks to increase fitness and survival. SCLC cells can easily transition from specialists that optimize a single task to generalists that fall within the continuum, suggesting that phenotypic plasticity may be a mechanism by which SCLC cells become recalcitrant to treatment and adaptable to diverse microenvironments. We show that plasticity is uncoupled from the phenotype of single cells using a novel RNA-velocity-based metric, suggesting both specialist and generalist cells have the capability of becoming destabilized and transitioning to other phenotypes. We use network simulations to identify transcription factors such as MYC that promote plasticity and resistance to treatment. Our analysis pipeline is suitable to elucidate the role of phenotypic plasticity in any cancer type, and positions SCLC as a prime candidate for treatments that target plasticity.

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Section: Cell Transport Potential Calculation and Analysismentioning

confidence: 99%

Cancer Hallmarks Define a Continuum of Plastic Cell States between Small Cell Lung Cancer Archetypes

Ireland

et al. 2021

Preprint

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“…Recent studies using mouse models of cancer provided evidence of polyclonal seeding of cancer cells, which often disseminate in parallel to form metastases, and of cooperation between subclones to enhance tumor progression[60-63]. Phylogenetic analysis of matched samples from metastatic cancer patients corroborated those findings and demonstrated that metastasis-to-metastasis spread is a common event[64].…”

Section: Discussionmentioning

confidence: 99%

Patient-derived models of brain metastases recapitulate the histopathology and biology of human metastatic cancers

Faria

Custódia

Cascão

et al. 2020

Preprint

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PurposeDissemination of cancer cells from primary tumors to the brain is observed in the great majority of cancer patients, contributing to increased morbidity and being the main cause of death. Most mechanistic and preclinical studies have relied on aggressive cancer cell lines, which fail to represent tumor heterogeneity and are unsuitable to validate therapies due to fast cancer progression in vivo.Experimental designWe established a unique library of subcutaneous and intracardiac patient-derived xenografts (PDXs) of brain metastases (BMs) from eight distinct primary tumor origins. Cancer progression in mice was compared to the matched patient clinical outcome, metastatic dissemination pattern and histopathological features. Preclinical studies with FDA approved drugs were performed.ResultsIn vivo tumor formation of flank-implanted BMs correlated with patients’ poor survival and serial passaging increased tumor aggressiveness. Subcutaneous xenografts originated spontaneous metastases in 61% of the cases, including in the leptomeningeal space (21%). The intracardiac model increased the tropism to the brain and leptomeninges (46%). Strikingly, 62% of intracardiac PDXs shared metastatic sites with the donor patients, including the primary cancer organ and the central nervous system (CNS). Of therapeutic relevance, PDX-derived cultures and corresponding mouse xenografts can be effectively treated with targeted anticancer drugs.ConclusionsPatient-derived models of BMs recapitulate the biology of human metastatic disease and can be a valuable translational platform for precision medicine.TRANSLATIONAL RELEVANCESubcutaneous and intracardiac mouse xenografts of human brain metastases exhibit a spontaneous dissemination pattern that resembles patients’ metastatic disease. The preclinical testing of targeted anticancer drugs using patient-derived cultures and patient-derived xenografts of brain metastasis showed an effective therapeutic response. These translational models represent an outstanding tool to advance the understanding of the biology of brain metastases and to foster the rapid discovery of novel therapeutics.

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“…Adenocarcinomas can be produced by Kras -G12D expression in AT2 cells expressing either Sftpc or Scgb1a1 ( CCSP ; CC10 ) [ 62 ]. Although Scgb1a1 is expressed in bronchiolar club cells in this model, they do not form invasive cancers [ 62 ] unless Trp53 mutations are introduced [ 63 , 64 ]. Lineage tracing in a Kras -G12 V model further showed that many alveolar cells expressing the mutant allele do not divide [ 65 ], suggesting heterogeneity among AT2 cells.…”

Section: Pre-clinical Nsclc Model Systemsmentioning

confidence: 99%

Progress towards non-small-cell lung cancer models that represent clinical evolutionary trajectories

et al. 2021

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Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. Although advances are being made towards earlier detection and the development of impactful targeted therapies and immunotherapies, the 5-year survival of patients with advanced disease is still below 20%. Effective cancer research relies on pre-clinical model systems that accurately reflect the evolutionary course of disease progression and mimic patient responses to therapy. Here, we review pre-clinical models, including genetically engineered mouse models and patient-derived materials, such as cell lines, primary cell cultures, explant cultures and xenografts, that are currently being used to interrogate NSCLC evolution from pre-invasive disease through locally invasive cancer to the metastatic colonization of distant organ sites.

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

Cited by 268 publications

References 100 publications

Cancer Hallmarks Define a Continuum of Plastic Cell States between Small Cell Lung Cancer Archetypes

Cancer Hallmarks Define a Continuum of Plastic Cell States between Small Cell Lung Cancer Archetypes

Patient-derived models of brain metastases recapitulate the histopathology and biology of human metastatic cancers

Progress towards non-small-cell lung cancer models that represent clinical evolutionary trajectories

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