Where Ideas Grow

Intercellular Communication and Cancer


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. The major goal of our research group is to understand the biological significance of communication among cells of the tumor microenvironment, and determine how it influences cancer onset, progression, and clinical response. Our current focus is on the role of communication:
1) established with the immune system in shaping the genetic and expression landscape of cancer cells; and
2) mediated by extracellular vesicles (EVs) in disease progression and acquisition of resistance to therapy..



Our lab is interested in understanding how communication between cancer and immune cells triggers an immune response and allows escape from immunosurveillance. In a collaborative study, we have shown that the glycosylation profile of cancer cells is immunosuppressive and is a consequence of a selective effect of adaptive immunity (Cancer Immunol Res 8:1407-25, 2020). We have also found that there is a progressive loss of adaptive immune cells during the colorectal adenoma carcinoma sequence suggestive of a dysfunctional state of immune cell exhaustion that likely results from persistent antigen stimulation and chronic inflammation.

We identified for the first time an organized network of communication centered in EVs originated in cancer stem cells and demonstrated its significance in the biology of the tumor. This communication is a fundamental process for cooperation within the tumor and contributes to its plastic nature and resistance to therapy. In a collaborative study, we have demonstrated that exosomes can be used as delivery vehicles for therapies that target specific mutations in cancer cells (Nature 546:498-503, 2017).

We are also testing the hypothesis that mutation-driven resistance to therapy is transferred from therapy-resistant to therapy-sensitive cancer cells. We have data showing that intercellular communication, either EV-mediated or through cell-free molecules, plays a key role in the process. Our results question the established concept that acquisition of resistance to targeted therapies relies solely on the selection of tumor cells carrying a specific resistance mutation, which is then passed on to its progeny through cell division.

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.


Selected Publications

Adem B., Vieira P.F., Melo S.A.,
Decoding the Biology of Exosomes in Metastasis. Trends in Cancer6(1):20-30, 2020. [Journal: Review] [CI: 26] [IF: 11,1 (*)]
DOI: 10.1016/j.trecan.2019.11.007 SCOPUS: 85076252541

Marques J.F., Junqueira-Neto S., Pinheiro J., Machado J.C., Costa J.L.,
Induction of apoptosis increases sensitivity to detect cancer mutations in plasma. European Journal of Cancer127:130-138, 2020. [Journal: Article] [CI: 6] [IF: 9,2]
DOI: 10.1016/j.ejca.2019.12.023 SCOPUS: 85078673234

Silva M.C., Fernandes Â., Oliveira M., Resende C., Correia A., de-Freitas-Junior J.C., Lavelle A., Andrade-Da-Costa J., Leander M., Xavier-Ferreira H., Bessa J., Pereira C., Henrique R.M., Carneiro F., Dinis-Ribeiro M., Marcos-Pinto R., Lima M., Lepenies B., Sokol H., Machado J.C., Vilanova M., Pinho S.S.,
Glycans as immune checkpoints: Removal of branched N-glycans enhances immune recognition preventing cancer progression. Cancer Immunology Research8(11):1407-1425, 2020. [Journal: Article] [CI: 18] [IF: 11,2]
DOI: 10.1158/2326-6066.CIR-20-0264 SCOPUS: 85100138005

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. [Journal: Article] [CI: 33] [IF: 7,1]
DOI: 10.1007/s10120-018-0836-8 SCOPUS: 85047119532

Fernandes M.G.O., Jacob M., Martins N., Moura C.S., Guimarães S., Reis J.P., Justino A., Pina M.J., Cirnes L., Sousa C., Pinto J., Marques J.A., Machado J.C., Hespanhol V., Costa J.L.,
Targeted gene next-generation sequencing panel in patients with advanced lung adenocarcinoma: Paving the way for clinical implementation. Cancers11(9):, 2019. [Journal: Article] [CI: 21] [IF: 6,1]
DOI: 10.3390/cancers11091229 SCOPUS: 85071868403

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. [Journal: Review] [CI: 118] [IF: 4,7]
DOI: 10.3389/fimmu.2018.00730 SCOPUS: 85045285386

Vaughn C.P., Costa J.L., Feilotter H.E., Petraroli R., Bagai V., Rachiglio A.M., Marino F.Z., Tops B., Kurth H.M., Sakai K., Mafficini A., Bastien R.R.L., Reiman A., Le Corre D., Boag A., Crocker S., Bihl M., Hirschmann A., Scarpa A., Machado J.C., Blons H., Sheils O., Bramlett K., Ligtenberg M.J.L., Cree I.A., Normanno N., Nishio K., Laurent-Puig P.,
Simultaneous detection of lung fusions using a multiplex RT-PCR next generation sequencing-based approach: A multi-institutional research study. BMC Cancer18(1):, 2018. [Journal: Article] [CI: 17] [IF: 2,9]
DOI: 10.1186/s12885-018-4736-4 SCOPUS: 85051742631

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. [Journal: Article] [CI: 1268] [IF: 41,6]
DOI: 10.1038/nature22341 SCOPUS: 85021081225

Yang S., Che S.P.Y., Kurywchak P., Tavormina J.L., Gansmo L.B., Correa de Sampaio P., Tachezy M., Bockhorn M., Gebauer F., Haltom A.R., Melo S.A., LeBleu V.S., Kalluri R.,
Detection of mutant KRAS and TP53 DNA in circulating exosomes from healthy individuals and patients with pancreatic cancer. Cancer Biology and Therapy18(3):158-165, 2017. [Journal: Article] [CI: 150] [IF: 3,4]
DOI: 10.1080/15384047.2017.1281499 SCOPUS: 85013638276

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. [Journal: Article] [CI: 20] [IF: 5,5]
DOI: 10.1007/s10120-014-0448-x SCOPUS: 84951569926

Ongoing Projects

Glycosylation and cancer: immunosurveillance’s sweet spot
Reference: EXPL/MED-ONC/1592/2021
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: FCT - Fundação para a Ciência e a Tecnologia
From 01-JAN-22 to 30-JUN-23
An artificially intelligent diagnostic assistant for gastric inflammation
Reference: HORIZON-HLTH-2022-STAYHLTH-02-01-RIA- GA 101095359
Proponent: Fundacion Incliva
Sponsor: CE - Comissão Europeia
From 01-JAN-23 to 31-DEC-26
PSGL-1 immune checkpoint protein antibody blockade as a strategy to increase T-cell responses against lymphoma
Reference: Bolsa APCL-SPH-Gilead 2022 - PROBLOCK
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: Associação Portuguesa contra a Leucemia
From 01-DEC-22 to 30-NOV-23
New Therapeutic Biomarkers in mGC
Reference: HORGAN-FC
Proponent: Ipatimup
Sponsor: Industry
From 01-AUG-16 to 31-JUL-23
Understand the contribution of Extracellular Vesicles for the establishment of a pancreatic cancer METastatic niche at the liver – the EVMet
Reference: 2022.01036.PTDC
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: FCT - Fundação para a Ciência e a Tecnologia
From 01-JAN-23 to 30-JUN-24
Decode the EVs Communication Map that Defines the Landscape of CAFs in Pancreatic Cancer
Reference: 2022.02284.PTDC
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: FCT - Fundação para a Ciência e a Tecnologia
From 01-FEB-23 to 31-JAN-26
CeLac and European consortium for a personalized medicine approach to Gastric Cancer
Reference: 825832
Proponent: Ipatimup
Sponsor: European Comission
From 01-JAN-19 to 30-JUN-23
Influence of an optimized combined dietary and exercise intervention on cytokine profile and NK cell infiltration of the tumor: an exploratory pilot study
Reference: ExDiet
Proponent: Ipatimup
Sponsor: SPG
From 01-JUN-19 to 31-MAY-23