Publications by authors named "David Papadopoli"

12 Publications

  • Page 1 of 1

Cell size homeostasis is maintained by CDK4-dependent activation of p38 MAPK.

Dev Cell 2021 Jun 21;56(12):1756-1769.e7. Epub 2021 May 21.

Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1A8, Canada; Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada. Electronic address:

While molecules that promote the growth of animal cells have been identified, it remains unclear how such signals are orchestrated to determine a characteristic target size for different cell types. It is increasingly clear that cell size is determined by size checkpoints-mechanisms that restrict the cell cycle progression of cells that are smaller than their target size. Previously, we described a p38 MAPK-dependent cell size checkpoint mechanism whereby p38 is selectively activated and prevents cell cycle progression in cells that are smaller than a given target size. In this study, we show that the specific target size required for inactivation of p38 and transition through the cell cycle is determined by CDK4 activity. Our data suggest a model whereby p38 and CDK4 cooperate analogously to the function of a thermostat: while p38 senses irregularities in size, CDK4 corresponds to the thermostat dial that sets the target size.
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http://dx.doi.org/10.1016/j.devcel.2021.04.030DOI Listing
June 2021

The role of GSK3 in metabolic pathway perturbations in cancer.

Biochim Biophys Acta Mol Cell Res 2021 Jul 12;1868(8):119059. Epub 2021 May 12.

Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1E2, Canada; Gerald Bronfman Department of Oncology, McGill University, 5100 Maisonneuve Blvd West, Montréal, QC H4A 3T2, Canada; Department of Medicine, Division of Experimental Medicine, McGill University, 1001 Décarie Blvd, Montréal, QC H4A 3J1, Canada; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montréal, QC H3G 1Y6, Canada.

Malignant transformation and tumor progression are accompanied by significant perturbations in metabolic programs. As such, cancer cells support high ATP turnover to construct the building blocks needed to fuel neoplastic growth. The coordination of metabolic networks in malignant cells is dependent on the collaboration with cellular signaling pathways. Glycogen synthase kinase 3 (GSK3) lies at the convergence of several signaling axes, including the PI3K/AKT/mTOR, AMPK, and Wnt pathways, which influence cancer initiation, progression and therapeutic responses. Accordingly, GSK3 modulates metabolic processes, including protein and lipid synthesis, glucose and mitochondrial metabolism, as well as autophagy. In this review, we highlight current knowledge of the role of GSK3 in metabolic perturbations in cancer.
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http://dx.doi.org/10.1016/j.bbamcr.2021.119059DOI Listing
July 2021

Perturbations of cancer cell metabolism by the antidiabetic drug canagliflozin.

Neoplasia 2021 04 27;23(4):391-399. Epub 2021 Mar 27.

Department of Biochemistry, McGill University, Montréal, QC, Canada; Departments of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada; Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada. Electronic address:

Notwithstanding that high rates of glucose uptake and glycolysis are common in neoplasia, pharmacological efforts to inhibit glucose utilization for cancer treatment have not been successful. Recent evidence suggests that in addition to classical glucose transporters, sodium-glucose transporters (SGLTs) are expressed by cancers. We therefore investigated the possibility that SGLT inhibitors, which are used in treatment of type 2 diabetes, may exert antineoplastic activity by limiting glucose uptake. We show that the SGLT2 inhibitor canagliflozin inhibits proliferation of breast cancer cells. Surprisingly, the antiproliferative effects of canagliflozin are not affected by glucose availability nor by the level of expression of SGLT2. Canagliflozin reduces oxygen consumption and glutamine metabolism through the citric acid cycle. The antiproliferative effects of canagliflozin are linked to inhibition of glutamine metabolism that fuels respiration, which represents a previously unanticipated mechanism of its potential antineoplastic action.
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http://dx.doi.org/10.1016/j.neo.2021.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027095PMC
April 2021

Cancer Plasticity: The Role of mRNA Translation.

Trends Cancer 2021 02 13;7(2):134-145. Epub 2020 Oct 13.

Department of Oncology, University of Alberta, Edmonton, AB, Canada; Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada. Electronic address:

Tumor progression is associated with dedifferentiated histopathologies concomitant with cancer cell survival within a changing, and often hostile, tumor microenvironment. These processes are enabled by cellular plasticity, whereby intracellular cues and extracellular signals are integrated to enable rapid shifts in cancer cell phenotypes. Cancer cell plasticity, at least in part, fuels tumor heterogeneity and facilitates metastasis and drug resistance. Protein synthesis is frequently dysregulated in cancer, and emerging data suggest that translational reprograming collaborates with epigenetic and metabolic programs to effectuate phenotypic plasticity of neoplasia. Herein, we discuss the potential role of mRNA translation in cancer cell plasticity, highlight emerging histopathological correlates, and deliberate on how this is related to efforts to improve understanding of the complex tumor ecology.
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http://dx.doi.org/10.1016/j.trecan.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023421PMC
February 2021

Genome-Wide Screens Reveal that Resveratrol Induces Replicative Stress in Human Cells.

Mol Cell 2020 09 4;79(5):846-856.e8. Epub 2020 Aug 4.

Institute for Research in Immunology and Cancer, Université de Montréal, PO Box 6128, Downtown Station, Montréal, QC H3C 3J7, Canada. Electronic address:

Resveratrol is a natural product associated with wide-ranging effects in animal and cellular models, including lifespan extension. To identify the genetic target of resveratrol in human cells, we conducted genome-wide CRISPR-Cas9 screens to pinpoint genes that confer sensitivity or resistance to resveratrol. An extensive network of DNA damage response and replicative stress genes exhibited genetic interactions with resveratrol and its analog pterostilbene. These genetic profiles showed similarity to the response to hydroxyurea, an inhibitor of ribonucleotide reductase that causes replicative stress. Resveratrol, pterostilbene, and hydroxyurea caused similar depletion of nucleotide pools, inhibition of replication fork progression, and induction of replicative stress. The ability of resveratrol to inhibit cell proliferation and S phase transit was independent of the histone deacetylase sirtuin 1, which has been implicated in lifespan extension by resveratrol. These results establish that a primary impact of resveratrol on human cell proliferation is the induction of low-level replicative stress.
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http://dx.doi.org/10.1016/j.molcel.2020.07.010DOI Listing
September 2020

Copper bioavailability is a KRAS-specific vulnerability in colorectal cancer.

Nat Commun 2020 07 24;11(1):3701. Epub 2020 Jul 24.

Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, 2950, Chemin de la Polytechnique, Montréal, QC, H3T 1J4, Canada.

Despite its importance in human cancers, including colorectal cancers (CRC), oncogenic KRAS has been extremely challenging to target therapeutically. To identify potential vulnerabilities in KRAS-mutated CRC, we characterize the impact of oncogenic KRAS on the cell surface of intestinal epithelial cells. Here we show that oncogenic KRAS alters the expression of a myriad of cell-surface proteins implicated in diverse biological functions, and identify many potential surface-accessible therapeutic targets. Cell surface-based loss-of-function screens reveal that ATP7A, a copper-exporter upregulated by mutant KRAS, is essential for neoplastic growth. ATP7A is upregulated at the surface of KRAS-mutated CRC, and protects cells from excess copper-ion toxicity. We find that KRAS-mutated cells acquire copper via a non-canonical mechanism involving macropinocytosis, which appears to be required to support their growth. Together, these results indicate that copper bioavailability is a KRAS-selective vulnerability that could be exploited for the treatment of KRAS-mutated neoplasms.
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http://dx.doi.org/10.1038/s41467-020-17549-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381612PMC
July 2020

PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis.

Nat Commun 2020 07 14;11(1):3520. Epub 2020 Jul 14.

Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore.

PRDM (PRDI-BF1 and RIZ homology domain containing) family members are sequence-specific transcriptional regulators involved in cell identity and fate determination, often dysregulated in cancer. The PRDM15 gene is of particular interest, given its low expression in adult tissues and its overexpression in B-cell lymphomas. Despite its well characterized role in stem cell biology and during early development, the role of PRDM15 in cancer remains obscure. Herein, we demonstrate that while PRDM15 is largely dispensable for mouse adult somatic cell homeostasis in vivo, it plays a critical role in B-cell lymphomagenesis. Mechanistically, PRDM15 regulates a transcriptional program that sustains the activity of the PI3K/AKT/mTOR pathway and glycolysis in B-cell lymphomas. Abrogation of PRDM15 induces a metabolic crisis and selective death of lymphoma cells. Collectively, our data demonstrate that PRDM15 fuels the metabolic requirement of B-cell lymphomas and validate it as an attractive and previously unrecognized target in oncology.
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http://dx.doi.org/10.1038/s41467-020-17064-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360777PMC
July 2020

Methotrexate elicits pro-respiratory and anti-growth effects by promoting AMPK signaling.

Sci Rep 2020 05 12;10(1):7838. Epub 2020 May 12.

Department of Biochemistry, McGill University, Montréal, QC, H3G 1Y6, Canada.

One-carbon metabolism fuels the high demand of cancer cells for nucleotides and other building blocks needed for increased proliferation. Although inhibitors of this pathway are widely used to treat many cancers, their global impact on anabolic and catabolic processes remains unclear. Using a combination of real-time bioenergetics assays and metabolomics approaches, we investigated the global effects of methotrexate on cellular metabolism. We show that methotrexate treatment increases the intracellular concentration of the metabolite AICAR, resulting in AMPK activation. Methotrexate-induced AMPK activation leads to decreased one-carbon metabolism gene expression and cellular proliferation as well as increased global bioenergetic capacity. The anti-proliferative and pro-respiratory effects of methotrexate are AMPK-dependent, as cells with reduced AMPK activity are less affected by methotrexate treatment. Conversely, the combination of methotrexate with the AMPK activator, phenformin, potentiates its anti-proliferative activity in cancer cells. These data highlight a reciprocal effect of methotrexate on anabolic and catabolic processes and implicate AMPK activation as a metabolic determinant of methotrexate response.
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http://dx.doi.org/10.1038/s41598-020-64460-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217946PMC
May 2020

mTOR as a central regulator of lifespan and aging.

F1000Res 2019 2;8. Epub 2019 Jul 2.

Département de Biochimie et Médecine Moléculaire, Université de Montréal, CP 6128, Succursale Centre-Ville, Montréal, QC, H3C 3J7, Canada.

The mammalian/mechanistic target of rapamycin (mTOR) is a key component of cellular metabolism that integrates nutrient sensing with cellular processes that fuel cell growth and proliferation. Although the involvement of the mTOR pathway in regulating life span and aging has been studied extensively in the last decade, the underpinning mechanisms remain elusive. In this review, we highlight the emerging insights that link mTOR to various processes related to aging, such as nutrient sensing, maintenance of proteostasis, autophagy, mitochondrial dysfunction, cellular senescence, and decline in stem cell function.
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http://dx.doi.org/10.12688/f1000research.17196.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611156PMC
June 2020

PGC-1α Promotes Breast Cancer Metastasis and Confers Bioenergetic Flexibility against Metabolic Drugs.

Cell Metab 2017 Nov 5;26(5):778-787.e5. Epub 2017 Oct 5.

Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada; Goodman Cancer Research Centre, McGill University, Montreal, QC H3G 1Y6, Canada. Electronic address:

Metabolic adaptations play a key role in fueling tumor growth. However, less is known regarding the metabolic changes that promote cancer progression to metastatic disease. Herein, we reveal that breast cancer cells that preferentially metastasize to the lung or bone display relatively high expression of PGC-1α compared with those that metastasize to the liver. PGC-1α promotes breast cancer cell migration and invasion in vitro and augments lung metastasis in vivo. Pro-metastatic capabilities of PGC-1α are linked to enhanced global bioenergetic capacity, facilitating the ability to cope with bioenergetic disruptors like biguanides. Indeed, biguanides fail to mitigate the PGC-1α-dependent lung metastatic phenotype and PGC-1α confers resistance to stepwise increases in metformin concentration. Overall, our results reveal that PGC-1α stimulates bioenergetic potential, which promotes breast cancer metastasis and facilitates adaptation to metabolic drugs.
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http://dx.doi.org/10.1016/j.cmet.2017.09.006DOI Listing
November 2017

The PGC-1α/ERRα Axis Represses One-Carbon Metabolism and Promotes Sensitivity to Anti-folate Therapy in Breast Cancer.

Cell Rep 2016 Feb 21;14(4):920-931. Epub 2016 Jan 21.

Goodman Cancer Research Centre, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada. Electronic address:

Reprogramming of cellular metabolism plays a central role in fueling malignant transformation, and AMPK and the PGC-1α/ERRα axis are key regulators of this process. The intersection of gene-expression and binding-event datasets for breast cancer cells shows that activation of AMPK significantly increases the expression of PGC-1α/ERRα and promotes the binding of ERRα to its cognate sites. Unexpectedly, the data also reveal that ERRα, in concert with PGC-1α, negatively regulates the expression of several one-carbon metabolism genes, resulting in substantial perturbations in purine biosynthesis. This PGC-1α/ERRα-mediated repression of one-carbon metabolism promotes the sensitivity of breast cancer cells and tumors to the anti-folate drug methotrexate. These data implicate the PGC-1α/ERRα axis as a core regulatory node of folate cycle metabolism and further suggest that activators of AMPK could be used to modulate this pathway in cancer.
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http://dx.doi.org/10.1016/j.celrep.2015.12.086DOI Listing
February 2016

PGC-1α supports glutamine metabolism in breast cancer.

Cancer Metab 2013 Dec 5;1(1):22. Epub 2013 Dec 5.

Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montréal, PQ H3A 1A3, Canada.

Background: Glutamine metabolism is a central metabolic pathway in cancer. Recently, reductive carboxylation of glutamine for lipogenesis has been shown to constitute a key anabolic route in cancer cells. However, little is known regarding central regulators of the various glutamine metabolic pathways in cancer cells.

Methods: The impact of PGC-1α and ERRα on glutamine enzyme expression was assessed in ERBB2+ breast cancer cell lines with quantitative RT-PCR, chromatin immunoprecipitation, and immunoblotting experiments. Glutamine flux was quantified using 13C-labeled glutamine and GC/MS analyses. Functional assays for lipogenesis were performed using 14C-labeled glutamine. The expression of glutamine metabolism genes in breast cancer patients was determined by bioinformatics analyses using The Cancer Genome Atlas.

Results: We show that the transcriptional coactivator PGC-1α, along with the transcription factor ERRα, is a positive regulator of the expression of glutamine metabolism genes in ERBB2+ breast cancer. Indeed, ERBB2+ breast cancer cells with increased expression of PGC-1α display elevated expression of glutamine metabolism genes. Furthermore, ERBB2+ breast cancer cells with reduced expression of PGC-1α or when treated with C29, a pharmacological inhibitor of ERRα, exhibit diminished expression of glutamine metabolism genes. The biological relevance of the control of glutamine metabolism genes by the PGC-1α/ERRα axis is demonstrated by consequent regulation of glutamine flux through the citric acid cycle. PGC-1α and ERRα regulate both the canonical citric acid cycle (forward) and the reductive carboxylation (reverse) fluxes; the latter can be used to support de novo lipogenesis reactions, most notably in hypoxic conditions. Importantly, murine and human ERBB2+ cells lines display a significant dependence on glutamine availability for their growth. Finally, we show that PGC-1α expression is positively correlated with that of the glutamine pathway in ERBB2+ breast cancer patients, and high expression of this pathway is associated with reduced patient survival.

Conclusions: These data reveal that the PGC-1α/ERRα axis is a central regulator of glutamine metabolism in ERBB2+ breast cancer. This novel regulatory link, as well as the marked reduction in patient survival time associated with increased glutamine pathway gene expression, suggests that targeting glutamine metabolism may have therapeutic potential in the treatment of ERBB2+ breast cancer.
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http://dx.doi.org/10.1186/2049-3002-1-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178216PMC
December 2013