Intercellular Communication and Cancer

Coordinator: José Carlos Machado

About the group

Tumors are composed of distinct subpopulations of cancer and non-cancer cells. Moreover, cancer cells invade, metastasize, and thrive in diverse niches in the host organism. These hallmarks of cancer reflect a high degree of plasticity of cancer cells and a systemic rather than a localized disease. Hence, understanding the communication network that connects all the cellular components of cancer provides a unique opportunity to translate basic research into clinically relevant information with impact on the capacity to deal with cancer progression, therapy resistance and, ultimately, improve patient survival. The major goal of our research group is to understand the spatiotemporal dynamics of intratumoral communication and how does it influence, and is influenced, by clinical events such as therapy and disease progression. Currently, we are investigating how intercellular communication mediated by extracellular vesicles and communication between cancer and immune cells shape plasticity of cancer cells.

Cells communicate with each other by delivering and incorporating extracellular vesicles (EVs) loaded with a repertoire of molecules that reflect the cell of origin. Genetic manipulation of cells to produce EVs labelled with different colours allows tracking of EVs into recipient cells.

Research

Our research is interdisciplinary and aims at developing integrated research at the interface between cancer biology, cancer genetics, cancer immunology and clinical application. By means of patient material, genetically engineered mouse models and in vitro models we challenge the canonical vision of mitosis-driven “vertical transmission” of traits between cancer cells through the study of extracellular vesicles-driven “horizontal transmission” of information and functional re-education of recipient cells. In addition, we aim to identify molecular factors involved in the interaction between stromal and cancer cells, and to study the impact of their inactivation on oncogenesis. We also investigate the interaction between cancer cells and the immune system with a focus on how cancer cells trigger an immune response and which mechanisms cancer cells use to subvert the immune response. The lab has strong expertise in molecular and cell biology approaches, uses several mouse models of colon, lung, pancreatic, gastric cancer and leukemia, and state-of-the-art technologies such as next generation sequencing, digital PCR, proteomics, advanced microscopy, and flow cytometry.

Selected Publications

Gullo I., Oliveira P., Athelogou M., Gonçalves G., Pinto M.L., Carvalho J., Valente A., Pinheiro H., Andrade S., Almeida G.M., Huss R., Das K., Tan P., Machado J.C., Oliveira C., Carneiro F. New insights into the inflamed tumor immune microenvironment of gastric cancer with lymphoid stroma: from morphology and digital analysis to gene expression. Gastric Cancer22(1):77-90, 2019.

Ghezzo M.N., Fernandes M.T., Pacheco-Leyva I., Rodrigues P.M., Machado R.S., Araújo M.A.S., Kalathur R.K., Futschik M.E., Alves N.L., Dos Santos N.R. FoxN1-dependent thymic epithelial cells promote T-cell leukemia development. Carcinogenesis39(12):1463-1476, 2018.

Barros F.M., Carneiro F., Machado J.C., Melo S.A. Exosomes and immune response in cancer: Friends or foes?. Frontiers in Immunology9(APR):, 2018.

Kamerkar S., Lebleu V.S., Sugimoto H., Yang S., Ruivo C.F., Melo S.A., Lee J.J., Kalluri R. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature546(7659):498-503, 2017.

Ruivo C.F., Adem B., Silva M., Melo S.A. The biology of cancer exosomes: Insights and new perspectives. Cancer Research77(23):6480-6488, 2017.

Resende C., Regalo G., Durães C., Pinto M.T., Wen X., Figueiredo C., Carneiro F., Machado J.C. Interleukin-1B signalling leads to increased survival of gastric carcinoma cells through a CREB-C/EBPß-associated mechanism. Gastric Cancer19(1):74-84, 2016.

Trinquand A., Dos Santos N.R., Quang C.T., Rocchetti F., Zaniboni B., Belhocine M., De Jesus C.D.C., 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 Discovery6(9):973-985, 2016.

Fernandes M.T., Ghezzo M.N., Silveira A.B., Kalathur R.K., Póvoa V., Ribeiro A.R., Brandalise S.R., Dejardin E., Alves N.L., Ghysdael J., Barata J.T., Yunes J.A., dos Santos N.R. Lymphotoxin-ß receptor in microenvironmental cells promotes the development of T-cell acute lymphoblastic leukaemia with cortical/mature immunophenotype. British Journal of Haematology171(5):736-751, 2015.

Justino A., Dias P., João Pina M., Sousa S., Cirnes L., Berta Sousa A., Carlos Machado J., Costa J.L. Comprehensive massive parallel DNA sequencing strategy for the genetic diagnosis of the neuro-cardio-facio-cutaneous syndromes. European Journal of Human Genetics23(3):347-353, 2015.

Durães C., Muñoz X., Bonet C., García N., Venceslá A., Carneiro F., Peleteiro B., Lunet N., Barros H., Lindkvist B., Boutron-Ruault M.C., Bueno-De-Mesquita H.B., Rizzato C., Trichopoulou A., Weiderpass E., Naccarati A., Travis R.C., Tjønneland A., Gurrea A.B., Johansson M., Riboli E., Figueiredo C., González C.A., Capellà G., MacHado J.C., Sala N. Genetic variants in the IL1A gene region contribute to intestinal-type gastric carcinoma susceptibility in European populations. International Journal of Cancer135(6):1343-1355, 2014.