To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated single-cell chromatin ...accessibility profiles and single-cell transcriptomes from 1,000 to 10,000 cells per sample for 48 polyps, 27 normal tissues and 6 CRCs collected from patients with or without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from homeostasis to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T cells and a subtype of pre-cancer-associated fibroblasts. In the cancerous state, we observe T cell exhaustion, RUNX1-regulated cancer-associated fibroblasts and increasing accessibility associated with HNF4A motifs in epithelia. DNA methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.
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 large-scale 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.
The Human Tumor Atlas Network outlines their ambitious plan to generate 3D, single-cell, multiparametric, and longitudinal maps of diverse tumor types.
The intestine is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota and affects overall ...health
. The intesting has a length of over nine metres, along which there are differences in structure and function
. The localization of individual cell types, cell type development trajectories and detailed cell transcriptional programs probably drive these differences in function. Here, to better understand these differences, we evaluated the organization of single cells using multiplexed imaging and single-nucleus RNA and open chromatin assays across eight different intestinal sites from nine donors. Through systematic analyses, we find cell compositions that differ substantially across regions of the intestine and demonstrate the complexity of epithelial subtypes, and find that the same cell types are organized into distinct neighbourhoods and communities, highlighting distinct immunological niches that are present in the intestine. We also map gene regulatory differences in these cells that are suggestive of a regulatory differentiation cascade, and associate intestinal disease heritability with specific cell types. These results describe the complexity of the cell composition, regulation and organization for this organ, and serve as an important reference map for understanding human biology and disease.
Regular exercise promotes whole-body health and prevents disease, but the underlying molecular mechanisms are incompletely understood
. Here, the Molecular Transducers of Physical Activity Consortium
...profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome and immunome in whole blood, plasma and 18 solid tissues in male and female Rattus norvegicus over eight weeks of endurance exercise training. The resulting data compendium encompasses 9,466 assays across 19 tissues, 25 molecular platforms and 4 training time points. Thousands of shared and tissue-specific molecular alterations were identified, with sex differences found in multiple tissues. Temporal multi-omic and multi-tissue analyses revealed expansive biological insights into the adaptive responses to endurance training, including widespread regulation of immune, metabolic, stress response and mitochondrial pathways. Many changes were relevant to human health, including non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health and tissue injury and recovery. The data and analyses presented in this study will serve as valuable resources for understanding and exploring the multi-tissue molecular effects of endurance training and are provided in a public repository ( https://motrpac-data.org/ ).
Mitochondria have diverse functions critical to whole-body metabolic homeostasis. Endurance training alters mitochondrial activity, but systematic characterization of these adaptations is lacking. ...Here, the Molecular Transducers of Physical Activity Consortium mapped the temporal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats trained for 1, 2, 4, or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart, and skeletal muscle. The colon showed non-linear response dynamics, whereas mitochondrial pathways were downregulated in brown adipose and adrenal tissues. Protein acetylation increased in the liver, with a shift in lipid metabolism, whereas oxidative proteins increased in striated muscles. Exercise-upregulated networks were downregulated in human diabetes and cirrhosis. Knockdown of the central network protein 17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) elevated oxygen consumption, indicative of metabolic stress. We provide a multi-omic, multi-tissue, temporal atlas of the mitochondrial response to exercise training and identify candidates linked to mitochondrial dysfunction.
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•Multi-omic atlas of the mitochondrial response to exercise training in 19 rat tissues•Robust temporal differences in mitochondrial response by -omes, tissues, and sex•Most dynamic responses in adrenal, brown adipose, colon, heart, liver, and muscle•Protein networks upregulated by exercise are downregulated in human T2D and cirrhosis
Amar et al. delineate the extensive molecular modifications occurring in mitochondria, central metabolic organelles, in response to endurance exercise training across diverse rat tissues. Their translational analysis suggests clinical relevance of the metabolic regulator HSD17B10. Its suppression induces metabolic stress in liver cells, underlining its potential role in disease pathology.
Endurance exercise training is known to reduce risk for a range of complex diseases. However, the molecular basis of this effect has been challenging to study and largely restricted to analyses of ...either few or easily biopsied tissues. Extensive transcriptome data collected across 15 tissues during exercise training in rats as part of the Molecular Transducers of Physical Activity Consortium has provided a unique opportunity to clarify how exercise can affect tissue-specific gene expression and further suggest how exercise adaptation may impact complex disease-associated genes. To build this map, we integrate this multi-tissue atlas of gene expression changes with gene-disease targets, genetic regulation of expression, and trait relationship data in humans. Consensus from multiple approaches prioritizes specific tissues and genes where endurance exercise impacts disease-relevant gene expression. Specifically, we identify a total of 5523 trait-tissue-gene triplets to serve as a valuable starting point for future investigations Exercise; Transcription; Human Phenotypic Variation.
Abstract
Aberrant shifts in DNA methylation have long been regarded as an early biomarker for cancer onset and progression. However, it is unclear when methylation aberrance starts and how it ...interacts with other epigenomic modifications. To address how epigenomic changes occur and interact during the transformation from normal healthy colon tissue to malignant colorectal cancer (CRC), we collected 51 samples from 15 familial adenomatous polyposis (FAP) and non-FAP colorectal cancer patients. We generated 30-70x of whole-genome enzymatic methylation sequencing (WGEM-seq) data via the novel Ultima Genomics ultra high-throughput sequencing platform. We observed hypermethylation and hypomethylation emerge early in the malignant transformation process in gene promoters and distal regulatory elements. We performed multifaceted analysis on methylation alterations with whole-genome sequencing (WGS), transposase accessibility (ATAC-seq), high-resolution chromatin accessibility (Tri-C), and gene expression (RNA-seq) data. Our multidimensional analysis demonstrates how collectively epigenomic alterations have affected gene expression throughout normal colon mucosa, benign and dysplasia polyps to adenocarcinoma. Epigenomic changes start as early as benign polyps, followed by other epigenomic shifts, including bivalent domains. Various epigenomic aberrances are associated with concomitant gene expression level changes. Our integrative analysis of multi-epigenomics data implicates collective and cumulative epigenomic instability in the early onset of colon carcinogenesis.
Citation Format: Hayan Lee, Gat Krieger, Tyson Clark, Yizhou Zhu, Aziz Khan, Casey R. Hanson, Aaron Horning, Edward D. Esplin, Mohan Badu, Kristina Paul, Roxanne Chiu, Bahareh Bahmani, Stephanie Nevins, Annika K. Weimer, Ariel Jaimovich, Christina Curtis, William Greenleaf, James M. Ford, Doron Lipson, Zohar Shipony, Michael P. Snyder. Familial adenomatous polyposis epigenetic landscape as a precancer model of colorectal cancer. abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4742.
Abstract
Familial adenomatous polyposis (FAP) patients develop hundreds of premalignant polyps that progress to colorectal cancer due to a germline mutation in the APC tumor suppressor. Polyps from ...FAP patients uniquely facilitate interrogation of the continuum of malignant transformation from histologically normal mucosa to benign and dysplastic polyps and eventual adenocarcinomas. As part of the Human Tumor Atlas Network (HTAN), we performed multi-omic profiling, including whole genome sequencing, on 135 samples from six FAP patients across the pre-malignant continuum spanning all physical regions of the large intestine, and serving as the most comprehensive FAP dataset available. Through a comparative analysis with a published FAP cohort (58 multi-region samples across 5 patients) and sporadic colorectal cancer cohort (n=57), each including benign and malignant samples, we evaluate the timing of driver acquisitions at each stage of malignant progression. Despite being separated by vast regions of histologically normal mucosa, independently evolving polyps show extensive mutation sharing, suggesting FAP polyps are polyclonal in origin. Finally, we leverage a simplified mechanistic model of embryonic colonic development demonstrating that the path to malignant transformation in FAP is consistent with polyclonal origins attributable to early mixing, perhaps as early as in-utero. Taken together, the HTAN FAP Atlas provides a novel window into the earliest stages of cancer formation and may illuminate barriers to malignant transformation and opportunities for earlier intervention.
Citation Format: Ryan O. Schenck, Aziz Khan, Aaron Horning, Edward D. Esplin, Emma Monte, Si Wu, Casey Hanson, Nasim Bararpour, Stephanie Neves, Lihua Jiang, Kévin Contrepois, Hayan Lee, Tuhin K. Guha, Zheng Hu, Rozelle Laquindanum, Meredith A. Mills, Hassan Chaib, Roxanne Chiu, Ruiqi Jian, Jeannie Chan, Mathew Ellenberger, Winston R. Becker, Bahareh Bahmani, Basil Michael, Jeanne Shen, Samuel Lancaster, Uri Ladabaum, Anshul Kundaje, Teri A. Longacre, William J. Greenleaf, James M. Ford, Michael P. Snyder, Christina Curtis. The polyclonal path to malignant transformation in familial adenomatous polyposis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3497.
Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training (ExT) and sex on its molecular ...landscape is not fully established. Utilizing an integrative multi-omics approach, and leveraging data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we show profound sexual dimorphism in the scWAT of sedentary rats and in the dynamic response of this tissue to ExT. Specifically, the scWAT of sedentary females displays -omic signatures related to insulin signaling and adipogenesis, whereas the scWAT of sedentary males is enriched in terms related to aerobic metabolism. These sex-specific -omic signatures are preserved or amplified with ExT. Integration of multi-omic analyses with phenotypic measures identifies molecular hubs predicted to drive sexually distinct responses to training. Overall, this study underscores the powerful impact of sex on adipose tissue biology and provides a rich resource to investigate the scWAT response to ExT.
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