bims-ectoca 2023-12-03 papers

Issue of 2023‒12‒03
four papers selected by
Ankita Daiya, BITS Pilani

bioRxiv. 2023 Nov 13. pii: 2023.11.09.566446. [Epub ahead of print]

Intrinsic epigenetic state of primary osteosarcoma drives metastasis.

Irtisha Singh, Nino Rainusso, Lyazat Kurenbekova, Bikesh K Nirala, Juan Dou, Abhinaya Muruganandham, Jason T Yustein.

Osteosarcoma (OS) is the most common primary malignant bone tumor affecting the pediatric population with high potential to metastasize to distal sites, most commonly the lung. Insights into defining molecular features contributing to metastatic potential are lacking. We have mapped the active chromatin landscapes of OS tumors by integrating histone H3 lysine acetylated chromatin (H3K27ac) profiles (n=13), chromatin accessibility profiles (n=11) and gene expression (n=13) to understand the differences in their active chromatin profiles and its impact on molecular mechanisms driving the malignant phenotypes. Primary OS tumors from patients with metastasis (primary met) have a distinct active chromatin landscape compared to primary tumors from patients without metastatic disease (localized). The difference in chromatin activity shapes the transcriptional profile of OS. We identified novel candidate genes involved in OS pathogenesis and metastasis, including PPP1R1B , PREX1 and IGF2BP1 , which exhibit increased chromatin activity in primary met along with higher transcript levels. Overall, differential chromatin activity in primary met occurs in proximity of genes regulating actin cytoskeleton organization, cellular adhesion, and extracellular matrix suggestive of their role in facilitating OS metastasis. Furthermore, chromatin profiling of tumors from metastatic lung lesions noted increases in chromatin activity in genes involved in cell migration and key intracellular signaling cascades, including the Wnt pathway. Thus, this data demonstrates that metastatic potential is intrinsically present in primary metastatic tumors and the cellular chromatin profiles further adapt to allow for successful dissemination, migration, and colonization at the distal metastatic site.

DOI: https://doi.org/10.1101/2023.11.09.566446

J Pathol. 2023 Nov 27.

Disruption of the TP53 locus in osteosarcoma leads to TP53 promoter gene fusions and restoration of parts of the TP53 signalling pathway.

Karim H Saba, Valeria Difilippo, Michal Kovac, Louise Cornmark, Linda Magnusson, Jenny Nilsson, Hilda van den Bos, Diana Cj Spierings, Mahtab Bidgoli, Tord Jonson, Vaiyapuri P Sumathi, Otte Brosjö, Johan Staaf, Floris Foijer, Emelie Styring, Michaela Nathrath, Daniel Baumhoer, Karolin H Nord.

TP53 is the most frequently mutated gene in human cancer. This gene shows not only loss-of-function mutations but also recurrent missense mutations with gain-of-function activity. We have studied the primary bone malignancy osteosarcoma, which harbours one of the most rearranged genomes of all cancers. This is odd since it primarily affects children and adolescents who have not lived the long life thought necessary to accumulate massive numbers of mutations. In osteosarcoma, TP53 is often disrupted by structural variants. Here, we show through combined whole-genome and transcriptome analyses of 148 osteosarcomas that TP53 structural variants commonly result in loss of coding parts of the gene while simultaneously preserving and relocating the promoter region. The transferred TP53 promoter region is fused to genes previously implicated in cancer development. Paradoxically, these erroneously upregulated genes are significantly associated with the TP53 signalling pathway itself. This suggests that while the classical tumour suppressor activities of TP53 are lost, certain parts of the TP53 signalling pathway that are necessary for cancer cell survival and proliferation are retained. In line with this, our data suggest that transposition of the TP53 promoter is an early event that allows for a new normal state of genome-wide rearrangements in osteosarcoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: TP53 intron 1; TP53 mutation; TP53 promoter; TP53 signalling pathway; gene fusion; osteosarcoma; p53; promoter swapping; separation-of-function mutation

DOI: https://doi.org/10.1002/path.6219

Epigenetics Chromatin. 2023 Nov 28. 16(1): 46

Chromatin balances cell redox and energy homeostasis.

Tamaki Suganuma, Jerry L Workman.

Chromatin plays a central role in the conversion of energy in cells: alteration of chromatin structure to make DNA accessible consumes energy, and compaction of chromatin preserves energy. Alteration of chromatin structure uses energy sources derived from carbon metabolism such as ATP and acetyl-CoA; conversely, chromatin compaction and epigenetic modification feedback to metabolism and energy homeostasis by controlling gene expression and storing metabolites. Coordination of these dual chromatin events must be flexibly modulated in response to environmental changes such as during development and exposure to stress. Aging also alters chromatin structure and the coordination of metabolism, chromatin dynamics, and other cell processes. Noncoding RNAs and other RNA species that associate directly with chromatin or with chromatin modifiers contribute to spatiotemporal control of transcription and energy conversion. The time required for generating the large amounts of RNAs and chromatin modifiers observed in super-enhancers may be critical for regulation of transcription and may be impacted by aging. Here, taking into account these factors, we review alterations of chromatin that are fundamental to cell responses to metabolic changes due to stress and aging to maintain redox and energy homeostasis. We discuss the relationship between spatiotemporal control of energy and chromatin function, as this emerging concept must be considered to understand how cell homeostasis is maintained.

Keywords: Aging; Cellular homeostasis; Chromatin modification; Energy; Metabolism

DOI: https://doi.org/10.1186/s13072-023-00520-8

Front Oncol. 2023 ;13 1272981

The permissive binding theory of cancer.

Caroline M Weisman.

The later stages of cancer, including the invasion and colonization of new tissues, are actively mysterious compared to earlier stages like primary tumor formation. While we lack many details about both, we do have an apparently successful explanatory framework for the earlier stages: one in which genetic mutations hold ultimate causal and explanatory power. By contrast, on both empirical and conceptual grounds, it is not currently clear that mutations alone can explain the later stages of cancer. Can a different type of molecular change do better? Here, I introduce the "permissive binding theory" of cancer, which proposes that novel protein binding interactions are the key causal and explanatory entity in invasion and metastasis. It posits that binding is more abundant at baseline than we observe because it is restricted in normal physiology; that any large perturbation to physiological state revives this baseline abundance, unleashing many new binding interactions; and that a subset of these cause the cellular functions at the heart of oncogenesis, especially invasion and metastasis. Significant physiological perturbations occur in cancer cells in very early stages, and generally become more extreme with progression, providing interactions that continually fuel invasion and metastasis. The theory is compatible with, but not limited to, causal roles for the diverse molecular changes observed in cancer (e.g. gene expression or epigenetic changes), as these generally act causally upstream of proteins, and so may exert their effects by changing the protein binding interactions that occur in the cell. This admits the possibility that molecular changes that appear quite different may actually converge in creating the same few protein complexes, simplifying our picture of invasion and metastasis. If correct, the theory offers a concrete therapeutic strategy: targeting the key novel complexes. The theory is straightforwardly testable by large-scale identification of protein interactions in different cancers.

Keywords: cancer epigenetic evolution; cancer evolution; evolutionary mechanism; invasion and metastasis; protein interactions; theory of cancer

DOI: https://doi.org/10.3389/fonc.2023.1272981