Regenerative Lineages and Immune-mediated Pruning in Lung Cancer Metastasis

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2020 Feb 12

PMID 32042191

Citations 207

Authors

Ashley M Laughney

Jing Hu

Nathaniel R Campbell

Samuel F Bakhoum

Manu Setty

Vincent-Philippe Lavallee

Yubin Xie

Ignas Masilionis

Ambrose J Carr

Sanjay Kottapalli

Viola Allaj

Marissa Mattar

Natasha Rekhtman

Joao B Xavier

Linas Mazutis

John T Poirier

Charles M Rudin

Dana Peer

Joan Massague

Affiliations

Soon will be listed here.

Abstract

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.

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