Background and Aims
Hepatocytes undergo profound metabolic rewiring when primed to proliferate during compensatory regeneration and in hepatocellular carcinoma (HCC). However, the metabolic control ...of these processes is not fully understood. In order to capture the metabolic signature of proliferating hepatocytes, we applied state‐of‐the‐art systems biology approaches to models of liver regeneration, pharmacologically and genetically activated cell proliferation, and HCC.
Approach and Results
Integrating metabolomics, lipidomics, and transcriptomics, we link changes in the lipidome of proliferating hepatocytes to altered metabolic pathways including lipogenesis, fatty acid desaturation, and generation of phosphatidylcholine (PC). We confirm this altered lipid signature in human HCC and show a positive correlation of monounsaturated PC with hallmarks of cell proliferation and hepatic carcinogenesis.
Conclusions
Overall, we demonstrate that specific lipid metabolic pathways are coherently altered when hepatocytes switch to proliferation. These represent a source of targets for the development of therapeutic strategies and prognostic biomarkers of HCC.
In conversation with Gerard Evan Dhillon, Paraminder; Evan, Gerard
The FEBS journal,
December 2019, 2019-12-00, 20191201, Letnik:
286, Številka:
24
Journal Article, Transcript
Recenzirano
Odprti dostop
Gerard Evan is Head of Department and Sir William Dunn Professor at the Department of Biochemistry, University of Cambridge, UK. Driven by his innate passion to understand how things work, Gerard has ...devoted much of his career to understanding the molecular basis of cancer, particularly the roles played by oncogenes such as Myc. His work has helped elucidate the complex role that this gene plays in cell proliferation and apoptosis, and paved new avenues for the treatment of aggressive cancers. In this interview, Gerard provides an overview of what is known about the role of Myc in normal and cancer cells and provides a persuasive argument for the application of ‘impersonalised therapy’ involving Myc inhibition as part of future chemotherapeutic drug regimes.
Gerard Evan is Head of the Dept of Biochemistry at the University of Cambridge (UK). His research in cancer biology has helped elucidate the complex role that the oncogene Myc plays in cell proliferation and apoptosis, and paved new avenues for the treatment of aggressive cancers. In this interview, Gerard provides an overview of what is known about the role of Myc in normal and cancer cells and provides a persuasive argument for the development of Myc‐focused chemotherapy.
It is unclear why some tissues are refractory to the mitogenic effects of the oncogene Myc. Here we show that Myc activation induces rapid transcriptional responses followed by proliferation in some, ...but not all, organs. Despite such disparities in proliferative response, Myc is bound to DNA at open elements in responsive (liver) and non-responsive (heart) tissues, but fails to induce a robust transcriptional and proliferative response in the heart. Using heart as an exemplar of a non-responsive tissue, we show that Myc-driven transcription is re-engaged in mature cardiomyocytes by elevating levels of the positive transcription elongation factor (P-TEFb), instating a large proliferative response. Hence, P-TEFb activity is a key limiting determinant of whether the heart is permissive for Myc transcriptional activation. These data provide a greater understanding of how Myc transcriptional activity is determined and indicate modification of P-TEFb levels could be utilised to drive regeneration of adult cardiomyocytes for the treatment of heart myopathies.
Taking a Back Door to Target Myc Evan, Gerard
Science (American Association for the Advancement of Science),
01/2012, Letnik:
335, Številka:
6066
Journal Article
Recenzirano
The oncogenic activity of the transcription factor Myc might be blocked by targeting nononcogenic proteins that Myc depends on to cause cancer.
The transcription factor Myc coordinates the expression ...of a vast and functionally diverse repertoire of thousands of genes that, together, are required for the orderly proliferation of somatic cells within the body. These include genes that govern processes within the cell, such as the cell division cycle, cell metabolism and biosynthesis, cell architecture, and cell survival, as well as the multitude of processes that proliferating cells need to engage in their surrounding microenvironment, such as the generation of blood vessels, tissue remodeling, and the recruitment of cells loaded with enzymes and growth factors needed to do this. Myc is functionally nonredundant and absolutely required for the efficient proliferation of normal and cancer cells. Its expression depends on growth signals in normal cells, ensuring that its growth-promoting activities are unleashed only in cells instructed to proliferate. Control of Myc expression in cancer cells is almost always compromised. Mutations that cause Myc to become hyperactived cause uncontrollable cell proliferation and tumor formation. However, Myc has proven to be an elusive target for drug development. On page 348 of this issue, Kessler
et al.
(
1
) provide insight into how Myc's oncogenic activity might be suppressed by targeting nononcogenic proteins whose functions help Myc to transform cells.
Deregulated Myc triggers a variety of intrinsic tumor suppressor programs that serve to restrain Myc's oncogenic potential. Since Myc activity is also required for normal cell proliferation, ...activation of intrinsic tumor suppression must be triggered only when Myc signaling is oncogenic. However, how cells discriminate between normal and oncogenic Myc is unknown. Here we show that distinct threshold levels of Myc govern its output in vivo: low levels of deregulated Myc are competent to drive ectopic proliferation of somatic cells and oncogenesis, but activation of the apoptotic and ARF/p53 intrinsic tumor surveillance pathways requires Myc overexpression. The requirement to keep activated oncogenes at a low level to avoid engaging tumor suppression is likely an important selective pressure governing the early stages of tumor microevolution.
The ups and downs of Myc biology Soucek, Laura; Evan, Gerard I
Current opinion in genetics & development,
02/2010, Letnik:
20, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The basic helix–loop–helix protein Myc is a renowned transcription factor controlling disparate aspects of cell physiology that, together, allow efficient proliferation of somatic cells. This ...ability, together with the observation that its deregulated expression occurs in the majority of human cancers, suggests that Myc could be a good therapeutic target. However, several aspects of Myc biology remain elusive: what is the major difference between oncogenic and physiological Myc? How does oncogenic Myc evade the intrinsic tumor surveillance pathways provided by evolution? If Myc inhibition were even possible, what would be the consequences for the homeostasis of normal proliferating tissues versus the fate of cancer cells? Here we summarize the latest works addressing these issues.
Cancers are rare because their evolution is actively restrained by a range of tumour suppressors. Of these p53 seems unusually crucial as either it or its attendant upstream or downstream pathways ...are inactivated in virtually all cancers. p53 is an evolutionarily ancient coordinator of metazoan stress responses. Its role in tumour suppression is likely to be a relatively recent adaptation, which is only necessary when large, long-lived organisms acquired the sufficient size and somatic regenerative capacity to necessitate specific mechanisms to reign in rogue proliferating cells. However, such evolutionary reappropriation of this venerable transcription factor entails compromises that restrict its efficacy as a tumour suppressor.
c-MYC: more than just a matter of life and death Pelengaris, Stella; Khan, Mike; Evan, Gerard
Nature reviews. Cancer,
200210, 2002-Oct, 2002-10-00, 20021001, Letnik:
2, Številka:
10
Journal Article
Recenzirano
Deregulated expression of c-MYC occurs in a broad range of human cancers and is often associated with poor prognosis, indicating a key role for this oncogene in tumour progression. However, as ...established human tumours often bear multiple genetic lesions, it is difficult to determine whether c-MYC is instrumental in the initiation/progression of the tumour, or indeed whether inactivating c-MYC would lead to tumour regression. Regulatable transgenic mouse models of oncogenesis have shed light on these issues and provide hope for effective cancer therapies.
Although restoration of p53 function is an attractive tumor-specific therapeutic strategy, it remains unclear whether p53 loss is required only for transition through early bottlenecks in ...tumorigenesis or also for maintenance of established tumors. To explore the efficacy of p53 reinstatement as a tumor therapy, we used a reversibly switchable p53 knockin (KI) mouse model that permits modulation of p53 status from wild-type to knockout, at will. Using the well-characterized
Eμ-myc lymphoma model, we show that p53 is spontaneously activated when restored in established
Eμ-myc lymphomas in vivo, triggering rapid apoptosis and conferring a significant increase in survival. Nonetheless, reimposition of p53 function potently selects for emergence of p53-resistant tumors through inactivation of p19
ARF
or p53. Our study provides important insights into the nature and timing of p53-activating signals in established tumors and how resistance to p53 evolves, which will aid in the optimization of p53-based tumor therapies.
The two oncogenes KRas and Myc cooperate to drive tumorigenesis, but the mechanism underlying this remains unclear. In a mouse lung model of KRasG12D-driven adenomas, we find that co-activation of ...Myc drives the immediate transition to highly proliferative and invasive adenocarcinomas marked by highly inflammatory, angiogenic, and immune-suppressed stroma. We identify epithelial-derived signaling molecules CCL9 and IL-23 as the principal instructing signals for stromal reprogramming. CCL9 mediates recruitment of macrophages, angiogenesis, and PD-L1-dependent expulsion of T and B cells. IL-23 orchestrates exclusion of adaptive T and B cells and innate immune NK cells. Co-blockade of both CCL9 and IL-23 abrogates Myc-induced tumor progression. Subsequent deactivation of Myc in established adenocarcinomas triggers immediate reversal of all stromal changes and tumor regression, which are independent of CD4+CD8+ T cells but substantially dependent on returning NK cells. We show that Myc extensively programs an immune suppressive stroma that is obligatory for tumor progression.
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•Myc and Ras cooperate in vivo through the tumor microenvironment•Myc directly programs angiogenesis, inflammation, and immune suppression•IL-23 and CCL9 are cell non-autonomous effectors of Myc-driven lung carcinogenesis•Myc-driven tumor growth and maintenance depend on immune suppression
Oncogenic Myc activity orchestrates an immune suppressive tumor microenvironment.
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