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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

In the diabetic heart, chronic activation of the PPARalpha pathway drives excessive fatty acid (FA) oxidation, lipid accumulation, reduced glucose utilization, and cardiomyopathy. The related nuclear receptor, PPARbeta/delta, is also highly expressed in the heart, yet its function has not been fully delineated. To address its role in myocardial metabolism, we generated transgenic mice with cardiac-specific expression of PPARbeta/delta, driven by the myosin heavy chain (MHC-PPARbeta/delta mice). In striking contrast to MHC-PPARalpha mice, MHC-PPARbeta/delta mice had increased myocardial glucose utilization, did not accumulate myocardial lipid, and had normal cardiac function. Consistent with these observed metabolic phenotypes, we found that expression of genes involved in cellular FA transport were activated by PPARalpha but not by PPARbeta/delta. Conversely, cardiac glucose transport and glycolytic genes were activated in MHC-PPARbeta/delta mice, but repressed in MHC-PPARalpha mice. In reporter assays, we showed that PPARbeta/delta and PPARalpha exerted differential transcriptional control of the GLUT4 promoter, which may explain the observed isotype-specific effects on glucose uptake. Furthermore, myocardial injury due to ischemia/reperfusion injury was significantly reduced in the MHC-PPARbeta/delta mice compared with control or MHC-PPARalpha mice, consistent with an increased capacity for myocardial glucose utilization. These results demonstrate that PPARalpha and PPARbeta/delta drive distinct cardiac metabolic regulatory programs and identify PPARbeta/delta as a potential target for metabolic modulation therapy aimed at cardiac dysfunction caused by diabetes and ischemia.

Our results reveal a molecular mechanism by which lipid overload-induced mitochondrial ROS generation causes mitochondrial dysfunction by inducing post-translational modifications of mitochondrial proteins that regulate mitochondrial dynamics. These findings provide a novel mechanism for mitochondrial dysfunction in lipotoxic cardiomyopathy.

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