creating a
healthier future

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

Ruivo C.F., Bastos N., Adem B., Batista I., Duraes C., Melo C.A., Castaldo S.A., Campos-Labori F., Moutinho-Ribeir P., Morão B., Costa-Pint A., Silva S., Osorio H., Ciordia S., Costa J.L., Goodrich D., Cavadas B., Pereira L., Kouzarides T., MacEdo G., Maio R., Carneiro F., Cravo M., Kalluri R., MacHado J.C., Melo S.A.,
Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression. Gut71(10):2043-2068, 2022. [Journal: Article] [CI: 43] [IF: 24,5]
DOI: 10.1136/gutjnl-2021-324994 SCOPUS: 85130807227

Costa e Silva M., Sucena I., Cirnes L., Machado J.C., Campainha S., Barroso A.,
KIF5B-MET fusion variant in non-small cell lung cancer. Pulmonology28(4):315-316, 2022. [Journal: Letter] [CI: 1] [IF: 11,7]
DOI: 10.1016/j.pulmoe.2022.02.001 SCOPUS: 85131442502

Malfertheiner P., Megraud F., Rokkas T., Gisbert J.P., Liou J.M., Schulz C., Gasbarrini A., Hunt R.H., Leja M., O’Morain C., Rugge M., Suerbaum S., Tilg H., Sugano K., El-Omar E.M., Agreus L., Bazzoli F., Bordin D., Loginov A.S., Mario F.D., Dinis-Ribeiro M., Engstrand L., Fallone C., Goh K.L., Graham D., Kuipers E.J., Kupcinskas J., Lanas A., Machado J.C., Mahachai V., Marshall B.J., Milosavljevic T., Moss S.F., Park J.Y., Niv Y., Rajilic-Stojanovic M., Ristimaki A., Smith S., Tepes B., Wu C.Y., Zhou L.,
Management of Helicobacter pylori infection: the Maastricht VI/Florence consensus report. Gut71(9):1724-1762, 2022. [Journal: Article] [CI: 279] [IF: 24,5]
DOI: 10.1136/gutjnl-2022-327745 SCOPUS: 85137345984

Freitas J.A., Gullo I., Garcia D., Miranda S., Spaans L., Pinho L., Reis J., Sousa F., Baptista M., Resende C., Leitão D., Durães C., Costa J.L., Carneiro F., Machado J.C.,
The adaptive immune landscape of the colorectal adenoma–carcinoma sequence. International Journal of Molecular Sciences22(18):, 2021. [Journal: Article] [CI: 4] [IF: 6,2]
DOI: 10.3390/ijms22189791 SCOPUS: 85114644531

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: 37] [IF: 14,2]
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: 8] [IF: 9,2]
DOI: 10.1016/j.ejca.2019.12.023 SCOPUS: 85078673234

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: 22] [IF: 6,1]
DOI: 10.3390/cancers11091229 SCOPUS: 85071868403

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: 19] [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: 1594] [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: 172] [IF: 3,4]
DOI: 10.1080/15384047.2017.1281499 SCOPUS: 85013638276

Ongoing Projects

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
New Therapeutic Biomarkers in mGC
Reference: HORGAN-FC
Proponent: Ipatimup
Sponsor: Industry
From 01-AUG-16 to 31-JUL-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
Cellular architecture deconstructed: Artificial Intelligence to predict cancer invasion
Reference: 2022.02665.PTDC
Proponent: IST - Instituto Superior Técnico
Sponsor: FCT - Fundação para a Ciência e a Tecnologia
From 01-JAN-23 to 31-DEC-25
O papel das mutações somáticas na imunovigilância do cancro - MUSIC2
Reference: IPATIMUP - Donativo 2023 J.C.Machado - MUSIC2
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
From 01-JUL-23 to 30-JUN-25
Deciphering the impact of leukaemia on immunological fitness beyond disease
Reference: la Caixa HR23-00608
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: "la Caixa" Foundation
From 31-DEC-23 to 31-DEC-26
AI-Based personalised care for respiratory disease using multi-modal data in patient stratification
Reference: HORIZON-HLTH-2022-TOOL-12-01-RIA- GA 101080756
Proponent: INESC TEC
Sponsor: CE - Comissão Europeia
From 01-JAN-24 to 31-DEC-27