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.

Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous largescale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.Cancer forms and progresses through a series of critical transitions-from pre-malignant to malignant states, from locally contained to metastatic disease, and from treatment-responsive to treatment-resistant tumors (Figure 1). Although specifics differ across tumor types and patients, all transitions involve complex dynamic interactions between diverse pre-malignant, malignant, and non-malignant cells (e.g., stroma cells and immune cells), often organized in specific patterns within the tumor

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SignificanceIn plants, DNA cytosine methylation plays a central role in diverse cellular functions, from transcriptional regulation to maintenance of genome integrity. Vast numbers of whole-genome bisulphite sequencing (WGBS) datasets have been generated to profile DNA methylation at single-nucleotide resolution, yet computational analyses vary widely among research groups, making it difficult to cross-compare findings. Here we reprocessed hundreds of publicly available Arabidopsis WGBS libraries using a uniform pipeline. We identified high-confidence differentially methylated regions and compared libraries using a hierarchical framework, allowing us to identify relationships between methylation pathways. Furthermore, by using a large number of independent wild-type controls, we effectively filtered out spontaneous methylation changes from those that are biologically meaningful.

Calcification of soft tissues, such as heart valves and tendons, is a common clinical problem with limited therapeutics. Tissue specific stem/progenitor cells proliferate to repopulate injured tissues. But some of them become divergent to the direction of ossification in the local pathological microenvironment, thereby representing a cellular target for pharmacological approach. We observed that HIF-2alpha (encoded by EPAS1 inclined form) signaling is markedly activated within stem/progenitor cells recruited at calcified sites of diseased human tendons and heart valves. Proinflammatory microenvironment, rather than hypoxia, is correlated with HIF-2alpha activation and promoted osteochondrogenic differentiation of tendon stem/progenitor cells (TSPCs). Abnormal upregulation of HIF-2alpha served as a key switch to direct TSPCs differentiation into osteochondral-lineage rather than teno-lineage. Notably, Scleraxis (Scx), an essential tendon specific transcription factor, was suppressed on constitutive activation of HIF-2alpha and mediated the effect of HIF-2alpha on TSPCs fate decision. Moreover, pharmacological inhibition of HIF-2alpha with digoxin, which is a widely utilized drug, can efficiently inhibit calcification and enhance tenogenesis in vitro and in the Achilles's tendinopathy model. Taken together, these findings reveal the significant role of the tissue stem/progenitor cells fate decision and suggest that pharmacological regulation of HIF-2alpha function is a promising approach for soft tissue calcification treatment. STEM CELLS 2016;34:1083-1096 SIGNIFICANCE STATEMENTCalcification of soft tissues, such as heart valves and tendons, is a common public health concern with limited understanding and treatment options. Manipulating endogenous stem cells with small molecules has been proposed as a therapeutic strategy, but practical approaches are still unavailable. We have elucidated that HIF-2a acts as a crucial mediator of soft tissue calcification, by directly inhibiting Scx expression and regulating stem cells lineage differentiation. And we show that a pharmacological inhibitor of HIF-2a, digoxin, which is a widely utilized drug, can efficiently inhibit calcification and enhance tenogenesis in Achilles tendinopathy model. These findings are of great value on uncovering the mechanism of soft tissue calcification and developing future therapeutics based on tissue stem cells fate regulation.

The imminent release of tissue atlases combining multichannel microscopy with single-cell sequencing and other omics data from normal and diseased specimens creates an urgent need for data and metadata standards to guide data deposition, curation and release. We describe a Minimum Information about Highly Multiplexed Tissue Imaging (MITI) standard that applies best practices developed for genomics and for other microscopy data to highly multiplexed tissue images and traditional histology.

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