ORCID Profile
0000-0002-6254-0403
Current Organisations
University of Toronto
,
Lunenfeld-Tanenbaum Research Institute
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Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541625.V1
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541628
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541616
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541637
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541622.V1
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541631.V1
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 15-09-2022
DOI: 10.1158/2159-8290.CD-21-0865
Abstract: Infrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. In vivo CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of alveogenesis genes as potential early events in tumorigenesis. This article is highlighted in the In This Issue feature, p. 2711
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541631
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541625
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541634
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541622
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: MDPI AG
Date: 25-01-2023
Abstract: Receptor-interacting serine/threonine protein kinase 4 (RIPK4) and its kinase substrate the transcription factor interferon regulatory factor 6 (IRF6) play critical roles in the development and maintenance of the epidermis. In addition, ourselves and others have previously shown that RIPK4 is a NOTCH target gene that suppresses the development of cutaneous and head and neck squamous cell carcinomas (HNSCCs). In this study, we used autochthonous mouse models, where the expression of Pik3caH1047R oncogene predisposes the skin and oral cavity to tumor development, and show that not only loss of Ripk4, but also loss of its kinase substrate Irf6, triggers rapid SCC development. In vivo rescue experiments using Ripk4 or a kinase-dead Ripk4 mutant showed that the tumor suppressive function of Ripk4 is dependent on its kinase activity. To elucidate critical mediators of this tumor suppressive pathway, we performed transcriptional profiling of Ripk4-deficient epidermal cells followed by multiplexed in vivo CRISPR screening to identify genes with tumor suppressive capabilities. We show that Elovl4 is a critical Notch-Ripk4-Irf6 downstream target gene, and that Elovl4 loss itself triggers SCC development. Importantly, overexpression of Elovl4 suppressed tumor growth of Ripk4-deficient keratinocytes. Altogether, our work identifies a potent Notch1-Ripk4-Irf6-Elovl4 tumor suppressor axis.
Publisher: Elsevier BV
Date: 06-2020
DOI: 10.1016/J.CELL.2020.04.047
Abstract: Posterior fossa A (PFA) ependymomas are lethal malignancies of the hindbrain in infants and toddlers. Lacking highly recurrent somatic mutations, PFA ependymomas are proposed to be epigenetically driven tumors for which model systems are lacking. Here we demonstrate that PFA ependymomas are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation, and increase histone demethylation and acetylation at histone 3 lysine 27 (H3K27). PFA ependymomas initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3, and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA tumor growth. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541637.V1
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: Springer Science and Business Media LLC
Date: 31-05-2023
DOI: 10.1038/S41467-023-38841-7
Abstract: How the genetic landscape governs a tumor’s response to immunotherapy remains poorly understood. To assess the immune-modulatory capabilities of 573 genes associated with altered cytotoxicity in human cancers, here we perform CRISPR/Cas9 screens directly in mouse lung cancer models. We recover the known immune evasion factors Stat1 and Serpinb9 and identify the cancer testis antigen Adam2 as an immune modulator, whose expression is induced by Kras G12D and further elevated by immunotherapy. Using loss- and gain-of-function experiments, we show that ADAM2 functions as an oncogene by restraining interferon and TNF cytokine signaling causing reduced presentation of tumor-associated antigens. ADAM2 also restricts expression of the immune checkpoint inhibitors PDL1, LAG3, TIGIT and TIM3 in the tumor microenvironment, which might explain why ex vivo expanded and adoptively transferred cytotoxic T-cells show enhanced cytotoxic efficacy in ADAM2 overexpressing tumors. Together, direct in vivo CRISPR/Cas9 screens can uncover genetic alterations that control responses to immunotherapies.
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541634.V1
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549708.V1
Abstract: Abstract 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 a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent “long-tail” breast cancer genes, which revealed epigenetic regulation as a major tumor-suppressive mechanism. We report that components of the BAP1 and COMPASS-like complexes, including KMT2C/D, KDM6A, BAP1, and ASXL1/2 (“EpiDrivers”), cooperate with i PIK3CA /i sup H1047R /sup to transform mouse and human breast epithelial cells. Mechanistically, we find that activation of i PIK3CA /i sup H1047R /sup and concomitant EpiDriver loss triggered an alveolar-like lineage conversion of basal mammary epithelial cells and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. EpiDriver mutations are found in ∼39% of human breast cancers, and ∼50% of ductal carcinoma i in situ /i express casein, suggesting that lineage infidelity and alveogenic mimicry may significantly contribute to early steps of breast cancer etiology. Significance: Infrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. i In vivo /i CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of alveogenesis genes as potential early events in tumorigenesis. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-12-12-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 2711 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541616.V1
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Publisher: American Association for the Advancement of Science (AAAS)
Date: 13-03-2020
Abstract: Cancer genome–sequencing projects have emphasized the handful of genes mutated at high frequency in patients. Less attention has been directed to the hundreds of genes mutated in only a few patients—the so-called “long tail” mutations. Although rare, these mutations may nonetheless inform patient care. Loganathan et al. developed a reverse genetic CRISPR screen that allowed them to functionally assess in mice nearly 500 long tail gene mutations that occur in human head and neck squamous cell carcinoma (HNSCC). They identified 15 tumor-suppressor genes with activities that converged on the NOTCH signaling pathway. Given that NOTCH itself is mutated at high frequency in HNSCC, these results suggest that the growth of these tumors is largely driven by NOTCH inactivation. Science , this issue p. 1264
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.C.6549708
Abstract: Abstract 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 a somatic CRISPR/Cas9 mutagenesis screen to study 215 recurrent “long-tail” breast cancer genes, which revealed epigenetic regulation as a major tumor-suppressive mechanism. We report that components of the BAP1 and COMPASS-like complexes, including KMT2C/D, KDM6A, BAP1, and ASXL1/2 (“EpiDrivers”), cooperate with i PIK3CA /i sup H1047R /sup to transform mouse and human breast epithelial cells. Mechanistically, we find that activation of i PIK3CA /i sup H1047R /sup and concomitant EpiDriver loss triggered an alveolar-like lineage conversion of basal mammary epithelial cells and accelerated formation of luminal-like tumors, suggesting a basal origin for luminal tumors. EpiDriver mutations are found in ∼39% of human breast cancers, and ∼50% of ductal carcinoma i in situ /i express casein, suggesting that lineage infidelity and alveogenic mimicry may significantly contribute to early steps of breast cancer etiology. Significance: Infrequently mutated genes comprise most of the mutational burden in breast tumors but are poorly understood. i In vivo /i CRISPR screening identified functional tumor suppressors that converged on epigenetic regulation. Loss of epigenetic regulators accelerated tumorigenesis and revealed lineage infidelity and aberrant expression of alveogenesis genes as potential early events in tumorigenesis. i a href="ancerdiscovery/article/doi/10.1158/2159-8290.CD-12-12-ITI" target="_blank" This article is highlighted in the In This Issue feature, p. 2711 /a /i /
Publisher: Springer Science and Business Media LLC
Date: 05-09-2023
Publisher: MyJove Corporation
Date: 02-11-2020
DOI: 10.3791/61693
Publisher: American Association for the Advancement of Science (AAAS)
Date: 07-10-2022
Abstract: Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase (
Publisher: American Association for Cancer Research (AACR)
Date: 04-04-2023
DOI: 10.1158/2159-8290.22541628.V1
Abstract: Supplementary Data from Loss of Epigenetic Regulation Disrupts Lineage Integrity, Induces Aberrant Alveogenesis, and Promotes Breast Cancer
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Ahmad Ammar Malik.