Regenerative lineages and immune-mediated pruning in lung cancer metastasis

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 amongst 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 (NK) cells. Loss of developmental stage-specific constraint in macrometastases triggered by NK cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.

Single-cell analysis of human lung epithelia reveals concomitant expression of the SARS-CoV-2 receptor ACE2 with multiple virus receptors and scavengers in alveolar type II cells

“…Of note, most cells from the LUAD specimens clustered distinctly from cells of uninvolved lung tissues and exhibited the highest expression of the tumor marker CEACAM5 and mixed lineage genes ( Fig. 1b-c) thus representing diverse lung malignant cells in line with recent studies 26 .…”

CITEseq analysis of non-small-cell lung cancer lesions reveals an axis of immune cell activation associated with tumor antigen load andTP53mutations

“…The gene modules most upregulated in tumors compared to nlung included genes associated with glycolysis (mod39) and cell cycle (mod38), which were mainly expressed in MoDC cluster 52 ( Figure S2G-I). Frequent upregulation of many monocyte-or MΦ-like modules (7,3,4,6,5,37,10) was consistent with a higher frequency of MoDC compared to cDC in tumors.…”

“…Remaining cells with 3 unique α and β chains that could be uniquely associated with similar cells displaying 2 unique α and β chains were assumed to be clonally related, whereas cells that could be similarly associated with multiple distinct sets of cells expressing 2 unique α and β chains were excluded as doublets. 4. Cells in which a single TCR chain was observed were assumed to be clonally related to any cells with 2 unique α and β chains to which they uniquely associated.…”

Cancer-driven IgG promotes the development of castration-resistant Prostate Cancer though the SOX2-CIgG pathway

“…[31,32]. In addition, SOX2 as a stem-like transcription factor could promote EMT [32,33]. Therefore, our ndings provide a molecular bridge by which SOX2 promotes the progression of prostate cancer, suggesting a critical role for CIgG in the development of CRPC (Fig.…”