Journal Article

Regenerative lineages and immune-mediated pruning in lung cancer metastasis

Lavallée, Vincent-Philippe, Rekhtman, Natasha, Masilionis, Ignas, Pe’er, Dana, Allaj, Viola, Massagué, Joan, Laughney, Ashley M., Carr, Ambrose J., Xavier, Joao B., Poirier, John T., Setty, Manu, Rudin, Charles M., Hu, Jing, Campbell, Nathaniel R., Xie, Yubin, Kottapalli, Sanjay, Mattar, Marissa, Mazutis, Linas, Bakhoum, Samuel F.

2020

Overview

Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9 , and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9 -dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis. Single-cell analysis of lung cancer progression uncovers developmental and regenerative programs co-opted by cancer cells and immune-mediated pruning during metastatic outbreak

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67/1612/1350 / 631/67/2329 / Adenocarcinoma - immunology / Adenocarcinoma - pathology / Alveoli / Animals / Biomedical and Life Sciences / Biomedicine / Bronchi - metabolism / Cancer Research / Care and treatment / Cell Differentiation / Cell Lineage / Cluster Analysis / Complications and side effects / Databases, Genetic / Depletion / Developmental plasticity / Developmental stages / Disease Progression / Dormancy / Endoderm / Endoderm - metabolism / Female / Gene expression / Genetic aspects / Health aspects / Humans / Hydrogels - chemistry / Immune System - physiology / Immunosurveillance / Infectious Diseases / Killer Cells, Natural - metabolism / Lung - pathology / Lung cancer / Lung Neoplasms - immunology / Lung Neoplasms - pathology / Metabolic Diseases / Metastases / Metastasis / Mice / Molecular Medicine / Natural killer cells / Neoplasm Metastasis / Neurosciences / Outbreaks / Patient outcomes / Phenotype / Pruning / Pulmonary Alveoli - metabolism / Regeneration / Regenerative medicine / Signal Transduction / Sox9 protein / Tissue engineering / Transcription factors