Chromosomal instability (CIN) is a hallmark of cancer and it results from ongoing errors in chromosome segregation during mitosis. While CIN is a major driver of tumor evolution, its role in metastasis has not been established. Here we show that CIN promotes metastasis by sustaining a tumor-cell autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signaling. Genetic suppression of CIN significantly delays metastasis even in highly aneuploid tumor models, whereas inducing continuous chromosome segregation errors promotes cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumor cells co-opt chronic activation of innate immune pathways to spread to distant organs.

Therapeutic nanoparticles (TNPs) have shown heterogeneous responses in human clinical trials, raising the question of whether imaging should be used to identify patients with a higher likelihood of nanoparticle accumulation, and thus therapeutic response. Despite extensive debate about the enhanced permeability and retention (EPR) effect in tumors, it is increasingly clear that EPR is extremely variable yet little experimental data exists to predict its clinical utility. Based on the hypothesis that an FDA-approved 30-nm magnetic nanoparticle (MNP) could predict co-localization of therapeutic nanoparticles by MRI, we performed single-cell resolution imaging of fluorescently labeled MNPs and TNPs and studied their intratumoral distribution. We visualized MNPs circulating in tumor microvasculature and found sustained uptake into cells of the tumor microenvironment within minutes. MNPs could predictably demonstrate areas of co-localization for a model TNP [poly(D,L-lactic-co-glycolic acid)-b-polyethylene glycol; PLGA-b-PEG] within the tumor microenvironment (> 85% accuracy) and circulating within the microvasculature (>95% accuracy) despite their markedly different sizes and compositions. Computational analysis of NP transport enabled predictive modeling of TNP distribution based on imaging data, and identified key parameters governing intratumoral NP accumulation and macrophage uptake. Finally, MRI imaging accurately predicted initial treatment response and drug accumulation in a therapeutic study testing for the efficacy of paclitaxel-encapsulated nanoparticle. These approaches yield valuable insight into the in vivo kinetics of NP distribution and suggest that clinically-relevant imaging can be used to select patients with high EPR for treatment with TNPs.

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.