Research
Genetic Dynamics of Cancer Cells

Genetic Dynamics of Cancer Cells Lab

 

We are a young research group, which officially started in January 2014. We have an ambitious interdisciplinary research program and a highly motivated research team. Our research program is fully funded and we got a 100% success rate (3 out of 3) in the 2014 FCT Call for Project Grants. Our research laboratory is organized in three intimately related research lines centered on cancer genetics, exosomes biology and cancer microenvironment. Our research is interdisciplinary and aims at developing integrated research at the interface between cancer biology, cancer genetics, cancer immunology and clinical application. We are always looking for bright and highly motivated people who wish to pursue an internationally competitive scientific career.

 

 

 

 

The scientific question that drives our research group is how genetic information is transmitted among the diverse cellular constituents of a tumor, and how that impacts on the heterogeneity and plasticity of cancer cells. We want to understand how do mutations arise in cancer cells and how do they spread in cancer cell subpopulations. We want to understand how mutant or aberrantly expressed molecules impact on the interaction between cancer cells, and between cancer and non-cancer cells. We want to understand why cancer cell subpopulations fluctuate over time, and how does it influence, and is influenced, by clinical events such as therapy and disease progression.

We realize that tumor genetic heterogeneity is likely a key determinant of our understanding of tumor development and evolution, and that such diversity among cancer cells inside a tumor is often a confounder in tumor evaluation for diagnosis and treatment. Hence, the study of genetic dynamics of cancer cell populations provides a unique opportunity to translate basic research into clinically relevant information with impact on the capacity to deal with cancer progression, drug resistance and, ultimately, patient survival.

 

Cancer Genetics (PI: José Luís Costa)

 

Genetic alterations are a hallmark of tumor cells. Mitosis (“vertical transmission”) is the canonical mechanism to explain how gene mutations are transmitted to daughter cells, how cancer cell clones evolve and diverge and, ultimately, how cancer heterogeneity is generated. A complete knowledge of the genetic alterations present in tumor cells will contribute to our understanding of tumor initiation and progression, prognosis and therapy response. The aim of this research line is to identify and understand the dynamics of these genomic alterations in order to exploit and translate this knowledge for the clinical management of cancer patients. Our research is based on i) well-characterized patient material from our tumor-bank; ii) patient blood samples (liquid biopsy) for the characterization of cell-free nucleic acids and circulating tumor cells; iii) genetically engineered mouse models and on iv) state-of-the-art technology such as next generation sequencing and digital PCR.

 

Exosomes Biology (PI: Sónia Melo)

 

Exosomes are extracellular vesicles released by all cell types, enriched in nucleic acids, including mRNAs, non-coding RNAs and genomic DNA. Exosomes can transfer their cargo to adjacent recipient cells and/or distant organs and contribute to their phenotypic reprogramming. One of the lines of research of our lab is to study this “horizontal transmission” of information and how it contributes to the functional re-education of recipient cells. Our models are based on a vast collection of cancer cell lines from various organs, which allow us to fluorescently trace exosomes upon exocytosis in vitro as well as in vivo using orthotopic mouse models. Additionally, we also use transgenic mice models to evaluate the functional role of exosomes in cancer progression and metastatic dissemination. Finally, we have access to a vast collection of human samples from various cancers that allows us to validate our findings by studying exosomes of cancer patients in circulation.

 

Cancer Microenvironment (PI: Nuno Rodrigues dos Santos)

 

Oncogenesis is driven not only by genetic alterations intrinsic to cancer cells but also by molecular factors provided by genetically normal microenvironmental cells. The identification of stromal factors that participate in different phases of oncogenesis may provide complementary or alternative ways to treat malignancies. We aim therefore to identify molecular factors involved in the interaction between stromal and cancer cells, and to study the impact of their inactivation on oncogenesis. For this we use mainly genetically engineered mouse models, in vitro cellular systems, and mice xenografted with human cancer cells.

 

Cancer Immunosurveillance (PI: José Carlos Machado)

 

The consequences of mutations for cancer cells go far beyond the phenotype of the cancer cell itself. The interaction between cancer cells and the immune system constitutes a prime example. Immunosurveillance plays an essential role in the detection and destruction of early, clinically undetectable, neoplastic cells. Its efficacy depends on the ability to detect neoantigens, often generated through mutations. We use in vivo experiments with transgenic mice and human clinical samples to investigate how neoplastic cell mutations trigger immune response and which mechanisms neoplastic cells use to escape immunosurveillance.

 

Cancer Biomarkers (PI: Fátima Carneiro)

 

A product of the research our group conducts is the possibility to identify new cancer-associated genes and new biomarkers with diagnostic, prognostic or predictive value. The research objectives of the group include therefore the identification of genetic causes of cancer and the validation of biomarkers with clinical relevance. We are in an excellent position to do this due to our access to the Centro Hospitalar de São João tumor-bank, and due to our tight connections with diagnostic and clinical activities.

 

Selected publications from team members

 

  1. Trinquand A, Dos Santos NR*, Tran Quang C, Rocchetti F, Zaniboni B, Belhocine M, de Jesus CC, Lhermitte L, Tesio M, Dussiot M, Cosset F-L, Verhoeyen E, Pflumio F, Ifrah N, Dombret H, Spicuglia S, Chatenoud L, Gross D-A, Hermine O, Macintyre E, GhysdaeL J, Asnafi V. Triggering the TCR developmental checkpoint activates a therapeutically targetable tumor suppressive pathway in T-cell leukemia. Cancer Discov 6:972-85, 2016. *, first co-authorship.
  2. Resende C, Regalo G, Durães C, Pinto MT, Wen X, Figueiredo C, Carneiro F, Machado JC. Interleukin-1B signalling leads to increased survival of gastric carcinoma cells through a CREB-C/EBPß-associated mechanism. Gastric Cancer 19:74-84, 2016.
  3. Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, LeBleu VS, Mittendorf EA, Weitz J, Rahbari N, Reissfelder C, Pilarsky C, Fraga MF, Piwnica-Worms D, Kalluri R. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523: 177-82, 2015.
  4. Justino A, Dias P, João Pina M, Sousa S, Cirnes L, Berta Sousa A, Machado JC, Costa JL. Comprehensive massive parallel DNA sequencing strategy for the genetic diagnosis of the neuro-cardio-facio-cutaneous syndromes. Eur J Hum Genet 23: 347-53, 2015.
  5. Carneiro F, Grabsch H: Pathogenesis of gastric cancer. In: Minimally Invasive Foregut Surgery for Malignancy: Principles and Practice. Steven N Hochwald and Moshim Kukar (eds). Springer International Publishing Switzerland 2015, pp 61-72.
  6. Fernandes MT, Ghezzo MN, Silveira AB, Kalathur RK, Póvoa V, Ribeiro AR, Brandalise SR, Dejardin E, Alves NL, Ghysdael J, Barata JT, Yunes JA, Dos Santos NR. Lymphotoxin-ß receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype. Br J Haematol 171:736-51, 2015.
  7. Melo SA, Sugimoto H, O'Connell JT, Kato N, Villanueva A, Vidal A, Qiu L, Vitkin E, Perelman LT, Melo CA, Lucci A, Ivan C, Calin GA, Kalluri R. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 26:707-21, 2014.
  8. Kahlert C, Melo SA, Protopopov A, Tang J, Seth S, Koch M, Zhang J, Weitz J, Chin L, Futreal A, Kalluri R. Identification of Double Stranded Genomic DNA Spanning all Chromosomes with Mutated KRAS and p53 DNA in the Serum Exosomes of Patients with Pancreatic Cancer. J Biol Chem 289:3869-75, 2014.
  9. Durães C, Muñoz X, Bonet C, García N, Venceslá A, Carneiro F, Peleteiro B, Lunet N, Barros H, Lindkvist B, Boutron-Ruault MC, Bueno-de-Mesquita HB, Rizzato C, Trichopoulou A, Weiderpass E, Naccarati A, Travis R, Tjønneland A, Barricarte A, Johansson M, Riboli E, Figueiredo C, Gonzalez C, Capellà G, Machado JC, Sala N. "Genetic variants in the IL1A gene region contribute to intestinal-type gastric carcinoma susceptibility in European populations. Int J Cancer 135:1343-55, 2014.
  10. Costa JL, Sousa S, Justino A, Kay T, Fernandes S, Cirnes L, Schmitt F, Machado JC. Non Optical Massive Parallel DNA Sequencing of BRCA1 and BRCA2 Genes in a Diagnostic Setting. Hum Mutat 34:629-35, 2013.
  11. Melo CA, Drost J, Wijchers PJ, van de Werken H, de Wit E, Oude Vrielink JA, Elkon R, Melo SA, Léveillé N, Kalluri R, de Laat W, Agami R. eRNAs are required for p53-dependent enhancer activity and gene transcription. Mol Cell 49:524-35, 2013.
  12. Ferreira AC, Suriano G, Mendes N, Gomes B, Wen X, Carneiro F, Seruca R, Machado JC. E-cadherin impairment increases cell survival through Notch-dependent upregulation of Bcl-2 activation. Hum Mol Genet 21:334-343, 2012.
  13. Melo SA, Moutinho C, Ropero S, Calin GA, Rossi S, Spizzo R, Fernandez AF, Davalos V, Villanueva A, Montoya G, Yamamoto H, Schwartz S Jr, Esteller M. A genetic defect in exportin-5 traps precursor microRNAs in the nucleus of cancer cells. Cancer Cell 19:303-15, 2010.
  14. Lauwers GY, Carneiro F, Graham DY, Curado M-P, Franceschi S, Montgomery E, Tatematsu M, Hattori T: Gastric Carcinoma. In: WHO Classification of Tumours of the Digestive System, Fouth Edition. Bosman FT, Carneiro F, Hruban RH and Theise ND (eds), IARC Press: Lyon, 2010, pg 48-58.
  15. Elhai J, Kato M, Cousins S, Lindblad P, Costa JL. Very small mobile repeated elements in cyanobacterial genomes. Genome Res 18:1484-1499, 2008.
  16. Chin SF, Teschendorff AE, Marioni JC, Wang Y, Barbosa-Morais NL, Thorne NP, Costa JL, Pinder SE, van de Wiel MA, Green AR, Ellis IO, Porter PL, Tavaré S, Brenton JD, Ylstra B, Caldas C. High-resolution array-CGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer. Genome Biol 8: R215, 2007.
  17. van de Wiel M, Costa JL, Smid K, Oudejans C, Bergman A, Meijer G, Peters GJ, Ylstra B. Expression microarray analysis and oligo array CGH of acquired gemcitabine resistance in mouse colon reveals selection for chromosomal aberrations. Cancer Res 65: 10208-10213, 2005.
  18. Carneiro F, Huntsman DG, Smyrk TC, Owen DA, Seruca R, Pharoah P, Caldas C, Sobrinho-Simões M. Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening. J Pathol 203:681, 2004.
  19. Machado JC, Figueiredo C, Canedo P, Pharoah P, Carvalho R, Nabais S, Alves CC, Campos ML, van Doorn LJ, Caldas C, Seruca R, Carneiro F, Sobrinho-Simões M. A pro-inflammatory genetic profile increases the risk of chronic atrophic gastritis and gastric carcinoma. Gastroenterology 125: 364-371, 2003.
  20. Figueiredo C, Machado JC, Pharoah P, Seruca R, Sousa S, Carvalho R, Capelinha AF, Quint W, Caldas C, van Doorn LJ, Carneiro F, Sobrinho-Simões M. Helicobacter pylori and interleukin-1 genotyping: An opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst 94: 1680-1687, 2002.
  21. Huntsman DG, Carneiro F, Lewis FR, MacLeod PM, Hayashi A, Monaghan KG, Maung R, Seruca R, Jackson CE, Caldas C. Early gastric cancer in young, asymptomatic carriers of germ-line E-cadherin mutations. N Engl J Med 344:1904-9, 2001.
 
 
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