平特五不中

Lung Cancer

Prof. Logan Walsh and Dr. Jonathan Spicer co-lead the 平特五不中 Lung Cancer Research Network. Their research, along with other members of the network, is an important component of the Quebec Cancer Consortium (QCC) and Marathon of Hope Cancer Centres Network (MoHCCN).

Dr. Spicer recently co-led of one of the world鈥檚 most important clinical trials of immunotherapy for lung cancer in the neoadjuvant (pre-surgery) setting. This trial recently reported in the New England Journal of Medicine that the addition of pre-surgery immunotherapy significantly improved tumour responses and controlled patients鈥� cancers for longer than standard chemotherapy alone.

Studies led by Prof. Walsh are now using GCI spatial 鈥�-omics鈥� technology to analyze samples from this and other clinical trials in lung cancer at the single-cell level. This effort includes a ground-breaking computational analysis platform featuring machine learning and computer vision approaches, developed with GCI Associate Member Prof. Kaleem Siddiqui as well as GCI members Prof. Daniela Quail, Prof. Peter Siegel, and colleagues.

Their studies are leading to new biomarkers that can predict which patients will respond to cancer therapies such as immunotherapy and develop better ways to match patients with the best therapeutic strategies.

Publication highlights:

• Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. Forde PM, Spicer J, et al. N Engl J Med. 2022 May 26;386(21):1973-1985. doi: 10.1056/NEJMoa2202170 PMID: 35403841

• Machine learning meets classical computer vision for accurate cell identification. Karimi et al., BioRxiv. doi:

听

Prof. Spicer, along with Profs. Daniela Quail, Logan Walsh, and Lorenzo Ferri, have been instrumental in revealing the importance of neutrophils, a cell type of the innate immune system, in lung and other cancers. Their work has helped to establish that neutrophil extracellular traps (NETs), DNA- and protein-based structures released by activated neutrophils, mediate metastatic progression, including lung cancer metastasis.

Publication highlights:

• Neutrophil extracellular traps sequester circulating tumor cells via 尾1-integrin mediated interactions. Najmeh et al. Int J Cancer. 2017 May 15;140(10):2321-2330. doi: 10.1002/ijc.30635. PMID: 28177522
• Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects. Rayes et al. JCI Insight. 2019 Jul 25;5(16):e128008. doi: 10.1172/jci.insight.128008. PMID: 31343990
• Neutrophil oxidative stress mediates obesity-associated vascular dysfunction and metastatic transmigration. McDowell et al. Nat Cancer. 2021 May;2(5):545-562. doi: 10.1038/s43018-021-00194-9. PMID: 35122017

听

Prof. Sidong Huang has conducted a series of innovative studies on lung cancer using techniques known as 鈥渇unctional genomics鈥� 鈥� systematically inactivating each individual gene in the genomes of lung cancer cells to identify their vulnerabilities and discover new therapeutic targets. He leads the 平特五不中 Platform for Cellular Perturbation (MPCP), a pioneering technology platform that conducts functional genomics screens using a range of molecular tools, including CRISPR/Cas9 gene editing systems.

Publication highlights:

SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer. Xue Y, et al. Nat Commun. 2019 Feb 4;10(1):557. doi: 10.1038/s41467-019-08380-1. PMID: 30718506

CD44 Promotes PD-L1 Expression and Its Tumor-Intrinsic Function in Breast and Lung Cancers. Kong T, et al. Cancer Res. 2020 Feb 1;80(3):444-457. doi: 10.1158/0008-5472.CAN-19-1108. PMID: 31722999

SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca2+ flux to mitochondria. Xue Y, et al. Nat Commun. 2021 Sep 13;12(1):5404. doi: 10.1038/s41467-021-25260-9. PMID: 34518526

听

Prof. William Muller discovered that the cancer-causing gene ERBB2, or HER2, is activated in a proportion of lung cancers and other cancer types through a novel class of mutations that affect the way mature messenger RNA (mRNA) is produced from the ERBB2 gene, a process known as 鈥渁lternative splicing鈥�. Lung cancers that are caused by defects in ERBB2 alternative splicing may benefit from treatment with well-established anti-ERBB2 targeted therapies.

Publication highlights:

• An ErbB2 splice variant lacking exon 16 drives lung carcinoma. Smith HW, et al. Proc Natl Acad Sci U S A. 2020 Aug 18;117(33):20139-20148. doi: 10.1073/pnas.2007474117. PMID: 32727899

听

听

Pancreatic Cancer

Dr. George Zogopoulos is one of Canada鈥檚 leading hepato-pancreato-biliary surgeons and an expert in pancreatic cancer. He established the Quebec Pancreas Cancer Study, Quebec鈥檚 first prospective clinical research registry and biobank for pancreatic cancer. He is one of the lead investigators of EPPIC (Enhanced Pancreatic Cancer Profiling for Individualized Care), a Translational Research Program funded by the Terry Fox Research Institute that unites leading pancreatic cancer researchers from across Canada.

He is also an important contributor to other national and international pancreatic cancer research teams and consortia including Pancreatic Cancer Genetic Epidemiology Consortium (PACGENE), The Pancreatic Canadian Oncology Network (PancOne) and the Pancreatic Cancer Early Detection Consortium (PRECEDE), and he plays a leading role in the Quebec Cancer Consortium (QCC) and Marathon of Hope Cancer Centres Network (MoHCCN).

Dr. Zogopoulos鈥� lab pursues a program of translational research on pancreatic cancer that applies genomics to both patient samples and tumour models established directly from patient tumours. His studies are identifying the genetic changes that confer susceptibility to pancreatic cancer and drive its formation and progression, as well as revealing ways to match pancreatic cancer subtypes with the best treatment options.

Dr. Zogopoulos is also renowned for his skill and innovation in pancreatic surgical oncology and transplantation surgery, and he received the Michal & Renata Hornstein Career Award for Surgical Excellence in 2021.

Publication highlights:

• A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination-deficient Pancreatic Cancer. Wang Y, et al. Clin Cancer Res. 2020 Oct 15;26(20):5462-5476. doi: 10.1158/1078-0432.CCR-20-1439. PMID: 32816949
• A region-based gene association study combined with a leave-one-out sensitivity analysis identifies SMG1 as a pancreatic cancer susceptibility gene. Wong C, et al. PLoS Genet. 2019 Aug 30;15(8):e1008344. doi: 10.1371/journal.pgen.1008344. PMID: 31469826
• Reflex Testing for Germline BRCA1, BRCA2, PALB2, and ATM Mutations in Pancreatic Cancer: Mutation Prevalence and Clinical Outcomes From Two Canadian Research Registries. Smith AL, et al. JCO Precis Oncol. 2018 Nov;2:1-16. doi: 10.1200/PO.17.00098. PMID: 35135108

The GCI has made important contributions to understanding how changes in metabolism contribute to pancreatic cancer through collaborative studies which revealed new therapeutic targets in pancreatic cancer and uncovered fundamental mechanisms of pancreatic inflammation, which is an important predisposing factor to cancer and other pancreatic diseases.

These studies have been spearheaded at the GCI by the Metabolomics Innovation Resource (MIR), our ground-breaking technology platform for comprehensive metabolic profiling, under the leadership of Prof. Peter Siegel and Platform Manager Daina Avizonis, PhD. The MIR is supported by a Terry Fox New Frontiers Program Project Grant on "Targeting the Metabolic Vulnerabilities of Cancer" led by Prof. Peter Siegel, with the support of the Terry Fox Research Institute and the Quebec Breast Cancer Foundation. It has also been supported by major investments from the Canada Foundation for Innovation and the Dr. John R. and Mrs. Clara M. Fraser Trust.

Publication highlights, in collaboration with Prof. Christine Chio (Columbia University), Prof. Jerry Pelletier and Prof. Michael Pollak:

• eIF4A supports an oncogenic translation program in pancreatic ductal adenocarcinoma. Chan et al. Nat Commun. 2019 Nov 13;10(1):5151. doi: 10.1038/s41467-019-13086-5. PMID: 31723131 听from ).
• Methionine oxidation activates pyruvate kinase M2 to promote pancreatic cancer metastasis. He et al. Mol Cell. 2022 Aug 18;82(16):3045-3060.e11. doi: 10.1016/j.molcel.2022.06.005. Epub 2022 Jun 24. PMID: 35752173

Publication highlights, in collaboration with Prof. Nika Danial (Harvard University) and听Daina Avizonis:

• Glucose-dependent partitioning of arginine to the urea cycle protects 尾-cells from inflammation. Fu et al. Nat Metab. 2020 May;2(5):432-446. doi: 10.1038/s42255-020-0199-4. Epub 2020 May 11. PMID: 32694660
• Glucose metabolism and pyruvate carboxylase enhance glutathione synthesis and restrict oxidative stress in pancreatic islets. Fu et al. Cell Rep. 2021 Nov 23;37(8):110037. doi: 10.1016/j.celrep.2021.110037. PMID: 34818536

听

Prof. Nahum Sonenberg has contributed his world-renowned expertise on mRNA translation to several important studies of pancreatic cancer biology. These have uncovered mechanisms by which mRNA translation programs involved in cellular responses to stress contribute to pancreatic cancer development and progression.

Publication highlights:

• ATF4-mediated induction of 4E-BP1 contributes to pancreatic beta cell survival under endoplasmic reticulum stress. Yamaguchi et al. Cell Metab. 2008 Mar;7(3):269-76. doi: 10.1016/j.cmet.2008.01.008. PMID: 18316032 (collaboration led by Hisamitsu Ishihara and Yoshitomo Oka, Sendai University, Japan)
• 听
• NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer. Chio et al. Cell. 2016 Aug 11;166(4):963-976. doi: 10.1016/j.cell.2016.06.056. PMID: 27477511 (collaboration with the lab of Prof. David Tuveson, Cold Spring Harbor Laboratory)

听

听

Prof. Michel Tremblay, working with Prof. Jerry Pelletier, Dr. George Zogopoulos, and colleagues, discovered that tyrosine phosphatases, key proteins that control cellular signaling pathways, are important in regulating the function of dendritic cells, a key immune cell type involved in anti-tumour responses. They showed that drugs blocking the activity of these enzymes, known as PTP1B and TC-PTP, can boost the function of dendritic cells isolated from pancreatic cancer patients, which are normally defective. These findings suggest that targeting PTP1B and TC-PTP can be an important part of an immunotherapy strategy for pancreatic and other cancers. This is currently being pursued by Kanyr Pharma, a company co-founded by Prof. Tremblay.

• Downregulation of PTP1B and TC-PTP phosphatases potentiate dendritic cell-based immunotherapy through IL-12/IFN纬 signaling. Penafuerte C, et al. Oncoimmunology. 2017 Apr 28;6(6):e1321185. doi: 10.1080/2162402X.2017.1321185. PMID: 28680757

听

Gastric Cancer

Prof. Morag Park and Dr. Lorenzo Ferri have established a gastric cancer biobank including an important collection of patient-derived gastric cancer models (xenografts and organoids) that are an enabling resource for understanding the biology and treatment response of gastric cancer. They are members of STORMing Cancer, a consortium that includes scientists and clinicians from Canada, the U.S., Israel and the UK, and which received 拢20M from Cancer Research UK through their Cancer Grand Challenges program. Prof. Park and Dr. Ferri's research on gastric cancer is also supported through the Quebec Cancer Consortium (QCC) and Marathon of Hope Cancer Centres Network (MoHCCN).

They have also collaborated with Prof. Joseph Kinsella (Dept. of Biological Engineering, 平特五不中) to develop 3D bioprinted gastric cancer models using cells derived directly from patient tumour samples. These engineered 鈥渁rtificial tissue鈥� models recapitulate patient drug responses and are a highly promising resource for drug discovery efforts in gastric cancer.

• Alginate-gelatin-Matrigel hydrogels enable the development and multigenerational passaging of patient-derived 3D bioprinted cancer spheroid models. Flores-Torres S, et al. Biofabrication. 2021 Mar 10;13(2). doi: 10.1088/1758-5090/abdb87. PMID: 33440351

Prof. Park鈥檚 work has helped to establish that the cancer-causing gene MET, which she discovered, is a major driver of gastric cancer. She has also identified mechanisms of resistance to drugs that inhibit MET in gastric cancer models.

• Dynamic reprogramming of signaling upon met inhibition reveals a mechanism of drug resistance in gastric cancer. Lai AZ, et al. Sci Signal. 2014 Apr 22;7(322):ra38. doi: 10.1126/scisignal.2004839. PMID: 24757178

听