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The Establishment of a Lung Colonization Assay for Circulating Tumor Cell Visualization in Lung Tissues
Published on: June 16, 2018
Regenerative lineages and immune-mediated pruning in lung cancer metastasis
Ashley M Laughney1,2,3,4,5, Jing Hu1, Nathaniel R Campbell1,2,6
1Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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.
Insights
Cancer cells hijack normal lung regeneration pathways. Primary tumors show regenerative cells, while metastases exhibit primitive stem-like programs, conferring immune resistance and driving tumor spread.
Area of Science:
- Cancer Biology
- Developmental Biology
- Immunology
Background:
- Normal tissue regeneration processes are linked to cancer development.
- The role of these processes during tumor progression and immune surveillance is not fully understood.
Purpose of the Study:
- To investigate the enactment of regenerative processes in human lung adenocarcinomas.
- To understand the role of developmental transcription factors in tumor progression and metastasis.
- To explore the interplay between developmental plasticity and immune surveillance in metastasis.
Main Methods:
- Analysis of human primary lung adenocarcinomas.
- Characterization of transcription factor profiles in primary tumors and metastases.
- Utilized a mouse model for spontaneous metastatic outbreak from dormancy.
- Investigated natural killer cell resistance mechanisms.
Main Results:
- Primary lung adenocarcinomas exhibit regenerative cell types and aberrant transcription factor expression.
- Metastases are enriched in SOX2 and SOX9 transcription factors, recapitulating primitive progenitor states.
- SOX9 confers resistance to natural killer cells, and its loss of constraint in macrometastases is linked to immune cell depletion.
Conclusions:
- Tumor progression involves the re-emergence of developmental and regenerative programs.
- Specific transcription factors (SOX2, SOX9) are crucial for metastatic potential and immune evasion.
- A dynamic interplay exists between developmental plasticity and immune-mediated selection during metastasis.
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