Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer

Cancer Discovery, Journal Year: 2022, Volume and Issue: 12(12), P. 2930 - 2953

Published: Sept. 15, 2022

Systematically investigating the scores of genes mutated in cancer and discerning disease drivers from inconsequential bystanders is a prerequisite for precision medicine but remains challenging. Here, we developed somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent "long-tail" breast genes, which revealed epigenetic regulation as major tumor-suppressive mechanism. We report that components BAP1 COMPASS-like complexes, including KMT2C/D, KDM6A, BAP1, ASXL1/2 ("EpiDrivers"), cooperate with PIK3CAH1047R transform mouse human epithelial cells. Mechanistically, find activation concomitant EpiDriver loss triggered an alveolar-like lineage conversion basal mammary cells accelerated formation luminal-like tumors, suggesting origin luminal tumors. mutations are found ∼39% cancers, ∼50% ductal carcinoma situ express casein, infidelity alveogenic mimicry may significantly contribute early steps etiology. Infrequently comprise most mutational burden tumors poorly understood. In vivo CRISPR screening identified functional tumor suppressors converged on regulation. Loss regulators tumorigenesis aberrant expression alveogenesis potential events tumorigenesis. This article highlighted Issue feature, p. 2711.

Language: Английский

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Sequential mutations in exponentially growing populations

PLoS Computational Biology, Journal Year: 2023, Volume and Issue: 19(7), P. e1011289 - e1011289

Published: July 10, 2023

Stochastic models of sequential mutation acquisition are widely used to quantify cancer and bacterial evolution. Across manifold scenarios, recurrent research questions are: how many cells there with n alterations, long will it take for these appear. For exponentially growing populations, have been tackled only in special cases so far. Here, within a multitype branching process framework, we consider general mutational path where mutations may be advantageous, neutral or deleterious. In the biologically relevant limiting regimes large times small rates, derive probability distributions number, arrival time, mutations. Surprisingly, two quantities respectively follow Mittag-Leffler logistic regardless mutations’ selective effects. Our results provide rapid method assess altering fundamental division, death, rates impacts mutant cells. We highlight consequences rate inference fluctuation assays.

Language: Английский

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Reuniting philosophy and science to advance cancer research

Biological reviews/Biological reviews of the Cambridge Philosophical Society, Journal Year: 2023, Volume and Issue: 98(5), P. 1668 - 1686

Published: May 8, 2023

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, methodological framework. Without such framework, oncology will collect piecemeal results, with scant dialogue between the scientific communities studying cancer. We argue one important way forward in service of more successful through greater integration applied sciences (experimental clinical) conceptual theoretical approaches, informed by philosophical methods. By illustration, we explore six central themes: (i) role mutations cancer; (ii) clonal evolution cells; (iii) relationship multicellularity; (iv) tumour microenvironment; (v) immune system; (vi) stem cells. In each case, examine open questions literature methodology show benefit synergy for medical

Language: Английский

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Rare disease research workflow using multilayer networks elucidates the molecular determinants of severity in Congenital Myasthenic Syndromes

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Feb. 28, 2024

Abstract Exploring the molecular basis of disease severity in rare scenarios is a challenging task provided limitations on data availability. Causative genes have been described for Congenital Myasthenic Syndromes (CMS), group diverse minority neuromuscular junction (NMJ) disorders; yet explanation phenotypic differences remains unclear. Here, we present workflow to explore functional relationships between CMS causal and altered from each patient, based multilayer network community detection analysis complementary biomedical information by relevant sources, namely protein-protein interactions, pathways metabolomics. Our results show that can be ascribed personalized impairment extracellular matrix components postsynaptic modulators acetylcholine receptor (AChR) clustering. This work showcases how coupling with -omics provides explanations varying diseases; paving way sorting out similar cases other diseases.

Language: Английский

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The whole-genome panorama of cancer drivers

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2017, Volume and Issue: unknown

Published: Sept. 20, 2017

SUMMARY The advance of personalized cancer medicine requires the accurate identification mutations driving each patient’s tumor. However, to date, we have only been able obtain partial insights into contribution genomic events tumor development. Here, design a comprehensive approach identify driver in and whole-genome panorama across more than 2,500 tumors from 37 types cancer. This includes coding non-coding point mutations, copy number alterations other rearrangements somatic origin, potentially predisposing germline variants. We demonstrate that are at root virtually all tumors, with carrying on average 4.6 events. Most individual harbor unique combination drivers, uncover most frequent co-occurring Half genes affected by several mutations. In summary, described here provides answers fundamental questions genomics bridges gap between medicine.

Language: Английский

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