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

The acetylating enzyme, spermidine/spermine N 1 -acetyltransferase, participates in polyamine homeostasis by regulating polyamine export and catabolism. Previously, we reported that overexpression of the enzyme in cultured tumor cells and mice activates metabolic flux through the polyamine pathway and depletes the N 1 -acetyltransferase coenzyme and fatty acid precursor, acetyl-CoA. Here, we investigate this possibility in spermidine/spermine N 1 -acetyltransferase transgenic mice in which the enzyme is systemically overexpressed and in spermidine/spermine N 1 -acetyltransferase knock-out mice. Tissues of the former were characterized by increased N 1 -acetyltransferase activity, a marked elevation in tissue and urinary acetylated polyamines, a compensatory increase in polyamine biosynthetic enzyme activity, and an increase in metabolic flux through the polyamine pathway. These polyamine effects were accompanied by a decrease in white adipose acetyl-and malonyl-CoA pools, a major (20-fold) increase in glucose and palmitate oxidation, and a distinctly lean phenotype. In SSAT-ko mice, the opposite relationship between polyamine and fat metabolism was observed. In the absence of N 1 -acetylation of polyamines, there was a shift in urinary and tissue polyamines indicative of a decline in metabolic flux. This was accompanied by an increase in white adipose acetyl-and malonyl-CoA pools, a decrease in adipose palmitate and glucose oxidation, and an accumulation of body fat. The latter was further exaggerated under a high fat diet, where knock-out mice gained twice as much weight as wild-type mice. A model is proposed whereby the expression status of spermidine/spermine N 1 -acetyltransferase alters body fat accumulation by metabolically modulating tissue acetyl-and malonyl-CoA levels, thereby influencing fatty acid biosynthesis and oxidation.The polyamines putrescine (Put), 3 spermidine (Spd), and spermine (Spm) are known for their critical role in supporting cell proliferation, albeit in ways that have not yet been clearly defined. For the most part, polyamines do not incorporate into macromolecules but rather bind electrostatically to negatively charged molecules, such as DNA, RNA, and phospholipids. Thus, as metabolically distinct entities, homeostatic control of intracellular polyamines is critical to their role in supporting cell proliferation. This is achieved by effector systems that regulate biosynthesis, catabolism, uptake, and export of these molecules. The enzyme, spermidine/spermine N 1 -acetyltransferase (SSAT), catalyzes the transfer of acetyl groups from acetyl-CoA to the terminal amines of polyamines and, thus, readies the molecule for export or catabolism via polyamine oxidase. The enzyme is short lived, sensitively regulated by intracellular polyamine pools, and highly inducible by polyamine analogues and various cytotoxic agents (1, 2).Although most antiproliferative strategies targeting the polyamine pathway seek to deplete intracellular pools by inhibiting biosynthesis, we have been investigating t...

MR imaging enhancement of 2.0 or more times had high sensitivity (100%) for invasive carcinomas 8 mm or more in diameter, with moderate specificity (65%). Time-intensity curves showed no significant difference between enhancement of benign and malignant lesions.

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The enzyme spermidine/spermine N 1 -acetyltransferase (SSAT) regulates the catabolism and export of intracellular polyamines. We have previously shown that activation of polyamine catabolism by conditional overexpression of SSAT has antiproliferative consequences in LNCaP prostate carcinoma cells. Growth inhibition was causally linked to high metabolic flux arising from a compensatory increase in polyamine biosynthesis. Here we examined the in vivo consequences of SSAT overexpression in a mouse model genetically predisposed to develop prostate cancer. TRAMP (transgenic adenocarcinoma of mouse prostate) female C57BL/6 mice carrying the SV40 early genes (T/t antigens) under an androgen-driven probasin promoter were cross-bred with male C57BL/6 transgenic mice that systemically overexpress SSAT. At 30 weeks of age, the average genitourinary tract weights of TRAMP mice were ϳ4 times greater than those of TRAMP/SSAT bigenic mice, and by 36 weeks, they were ϳ12 times greater indicating sustained suppression of tumor outgrowth. Tumor progression was also affected as indicated by a reduction in the prostate histopathological scores. By immunohistochemistry, SV40 large T antigen expression in the prostate epithelium was the same in TRAMP and TRAMP/SSAT mice. Consistent with the 18-fold increase in SSAT activity in the TRAMP/SSAT bigenic mice, prostatic N 1 -acetylspermidine and putrescine pools were remarkably increased relative to TRAMP mice, while spermidine and spermine pools were minimally decreased due to a compensatory 5-7-fold increase in biosynthetic enzymes activities. The latter led to heightened metabolic flux through the polyamine pathway and an associated ϳ70% reduction in the SSAT cofactor acetylCoA and a ϳ40% reduction in the polyamine aminopropyl donor S-adenosylmethionine in TRAMP/SSAT compared with TRAMP prostatic tissue. In addition to elucidating the antiproliferative and metabolic consequences of SSAT overexpression in a prostate cancer model, these findings provide genetic support for the discovery and development of specific small molecule inducers of SSAT as a novel therapeutic strategy targeting prostate cancer.