Cancer Metastasis
ABOUT
Metastases account for more than 90% of cancer-related deaths. Understanding the biology of therapy-resistant metastatic clones is critical for the development of effective strategies to improve cancer patients’ survival.
The long-term goal of the Cancer Metastasis group is to study the molecular mechanisms underlying the metastatic cascade, focusing on the biological advantage given by cell adhesion to cancer cells, namely for their systemic dissemination, therapy resistance and homing in a distinct microenvironment.
RESEARCH
Cancer metastasis involve a series of sequential steps: i) epithelial-to-mesenchymal transition (EMT) of individual cells within the primary tumor leading to their intravasation, ii) systemic survival of such circulating tumor cells (CTCs) and, finally, iii) their ability for extravasation at distant sites, where mesenchymal-to-epithelial transition (MET) potentiates their proliferation into metastatic lesions. Historically, EMT has been shown to be crucial for invasive and circulating cancer cells.
However, it has been recently debated whether it plays actually a role for metastatic establishment. In fact, there are reports proposing that metastasis can directly derive from tumor-derived epithelial micro-emboli that break off from primary tumors, lodging into distal capillaries, where they initiate metastatic growth. These observations are exposing the cancer research community to a novel perspective concerning the metastatic process, in which patients with epithelial cancers may have CTCs retaining adhesion that are able to achieve distant colonization.
Accordingly, our own results and expertise led us to assume that proficient cell-cell adhesion is decisive to promote collective cell invasion, as well as survival of matrix-detached cancer cells, by inducing stem-like properties and by decreasing their oxidative stress, which will potentiate the success of the metastatic process. It is then the aim of the Cancer Metastasis group to understand how cell adhesion is involved in epithelial cancer metastasis, contributing towards the identification of new strategies to monitor this complex biological process and to hamper cell adhesion-mediated survival in metastatic cancer cells, as well as its associated molecular mechanisms.
Using breast cancer as the main model of study, we are focusing our activity to answer the following questions:
- How do alterations in cell adhesion during early EMT impact cell plasticity, invasive capacity and metastatic spreading?
- How does cell adhesion, and its induced-signaling pathways, contribute to the invasion-metastasis cascade?
- How do cancer cell clusters communicate with the metastatic microenvironment and how does this dynamic crosstalk coordinate and dictate colonization capacity?

Team
Selected Publications
Cadherin Expression Profiles Define Glioblastoma Differentiation and Patient Prognosis. Cancers16(13):, 2024. [Journal: Article] [CI: 1] [IF: 4.5 (*)]
DOI: 10.3390/cancers16132298 SCOPUS: 85198382503
Carvalho R., Santos L., Conde I., Leitão R., Ferreira H.R.S., Gomes C., Silva A.P., Schmitt F., Carvalho-Maia C., Lobo J., Jerónimo C., Paredes J., Ribeiro A.S.
Nerve growth factor inducible (VGF) is a secreted mediator for metastatic breast cancer tropism to the brain. Journal of Pathology264(2):132-147, 2024. [Journal: Article] [CI: 2] [IF: 5.6 (*)]
DOI: 10.1002/path.6319 SCOPUS: 85200032869
Fonseca I., Horta C., Ribeiro A.S., Sousa B., Marteil G., Bettencourt-Dias M., Paredes J.
Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype. Cell Death and Disease14(2):, 2023. [Journal: Article] [CI: 8] [IF: 9 (*)]
DOI: 10.1038/s41419-023-05618-1 SCOPUS: 85148266310
Faria L., Canato S., Jesus T.T., Gonçalves M., Guerreiro P.S., Lopes C.S., Meireles I., Morais-De-Sá E., Paredes J., Janody F.
Activation of an actin signaling pathway in pre-malignant mammary epithelial cells by P-cadherin is essential for transformation. DMM Disease Models and Mechanisms16(2):, 2023. [Journal: Article] [CI: 5] [IF: 4]
DOI: 10.1242/dmm.049652 SCOPUS: 85150628415
Noronha C., Ribeiro A.S., Taipa R., Leitão D., Schmitt F., Reis J., Faria C., Paredes J.
PD-L1 tumor expression is associated with poor prognosis and systemic immunosuppression in glioblastoma. Journal of Neuro-Oncology156(3):453-464, 2022. [Journal: Article] [CI: 6] [IF: 3,9]
DOI: 10.1007/s11060-021-03907-3 SCOPUS: 85123488111
Conceição F., Sousa D.M., Loessberg-Zahl J., Vollertsen A.R., Neto E., Søe K., Paredes J., Leferink A., Lamghari M.
A metastasis-on-a-chip approach to explore the sympathetic modulation of breast cancer bone metastasis. Materials Today Bio13:, 2022. [Journal: Article] [CI: 31] [IF: 8,2]
DOI: 10.1016/j.mtbio.2022.100219 SCOPUS: 85124535475
Conde I., Ribeiro A.S., Paredes J.
Breast Cancer Stem Cell Membrane Biomarkers: Therapy Targeting and Clinical Implications. Cells11(6):, 2022. [Journal: Review] [CI: 17] [IF: 6]
DOI: 10.3390/cells11060934 SCOPUS: 85126055218
Martins E.P., Gonçalves C.S., Pojo M., Carvalho R., Ribeiro A.S., Miranda-Gonçalves V., Taipa R., Pardal F., Pinto A.A., Custódia C., Faria C.C., Baltazar F., Sousa N., Paredes J., Costa B.M.
Cadherin-3 is a novel oncogenic biomarker with prognostic value in glioblastoma. Molecular Oncology16(14):2611-2631, 2022. [Journal: Article] [CI: 9] [IF: 6,6]
DOI: 10.1002/1878-0261.13162 SCOPUS: 85128783711
Pinto M.T., Ribeiro A.S., Conde I., Carvalho R., Paredes J.
The chick chorioallantoic membrane model: A new in vivo tool to evaluate breast cancer stem cell activity. International Journal of Molecular Sciences22(1):1-15, 2021. [Journal: Article] [CI: 19] [IF: 6,2]
DOI: 10.3390/ijms22010334 SCOPUS: 85098853386
Conceição F., Sousa D.M., Paredes J., Lamghari M.
Sympathetic activity in breast cancer and metastasis: partners in crime. Bone Research9(1):, 2021. [Journal: Review] [CI: 34] [IF: 13,4]
DOI: 10.1038/s41413-021-00137-1 SCOPUS: 85100589741
Noronha C., Ribeiro A.S., Taipa R., Castro D.S., Reis J., Faria C., Paredes J.
Cadherin expression and emt: A focus on gliomas. Biomedicines9(10):, 2021. [Journal: Review] [CI: 40] [IF: 4,8]
DOI: 10.3390/biomedicines9101328 SCOPUS: 85115999198
Carvalho R., Paredes J., Ribeiro A.S.
Impact of breast cancer cells´ secretome on the brain metastatic niche remodeling. Seminars in Cancer Biology60:294-301, 2020. [Journal: Review] [CI: 24] [IF: 15,7]
DOI: 10.1016/j.semcancer.2019.10.011 SCOPUS: 85075353035
Blair V.R., McLeod M., Carneiro F., Coit D.G., D'Addario J.L., van Dieren J.M., Harris K.L., Hoogerbrugge N., Oliveira C., van der Post R.S., Arnold J., Benusiglio P.R., Bisseling T.M., Boussioutas A., Cats A., Charlton A., Schreiber K.E.C., Davis J.L., Pietro M.d., Fitzgerald R.C., Ford J.M., Gamet K., Gullo I., Hardwick R.H., Huntsman D.G., Kaurah P., Kupfer S.S., Latchford A., Mansfield P.F., Nakajima T., Parry S., Rossaak J., Sugimura H., Svrcek M., Tischkowitz M., Ushijima T., Yamada H., Yang H.K., Claydon A., Figueiredo J., Paringatai K., Seruca R., Bougen-Zhukov N., Brew T., Busija S., Carneiro P., DeGregorio L., Fisher H., Gardner E., Godwin T.D., Holm K.N., Humar B., Lintott C.J., Monroe E.C., Muller M.D., Norero E., Nouri Y., Paredes J., Sanches J.M., Schulpen E., Ribeiro A.S., Sporle A., Whitworth J., Zhang L., Reeve A.E., Guilford P.
Hereditary diffuse gastric cancer: updated clinical practice guidelines. The Lancet Oncology21(8):e386-e397, 2020. [Journal: Review] [CI: 275] [IF: 41,3]
DOI: 10.1016/S1470-2045(20)30219-9 SCOPUS: 85088930288
Dionísio M.R., Vieira A.F., Carvalho R., Conde I., Oliveira M., Gomes M., Pinto M.T., Pereira P., Pimentel J., Souza C., Marques M.M.C., Duval da Silva V., Barroso A., Preto D., Cameselle-Teijeiro J.F., Schmitt F., Ribeiro A.S., Paredes J.
BR-BCSC Signature: The Cancer Stem Cell Profile Enriched in Brain Metastases that Predicts a Worse Prognosis in Lymph Node-Positive Breast Cancer. Cells9(11):, 2020. [Journal: Article] [CI: 11] [IF: 6,6]
DOI: 10.3390/cells9112442 SCOPUS: 85096082267
Sousa B., Pereira J., Marques R., Grilo L.F., Pereira S.P., Sardão V.A., Schmitt F., Oliveira P.J., Paredes J.
P-cadherin induces anoikis-resistance of matrix-detached breast cancer cells by promoting pentose phosphate pathway and decreasing oxidative stress. Biochimica et Biophysica Acta - Molecular Basis of Disease1866(12):, 2020. [Journal: Article] [CI: 25] [IF: 5,2]
DOI: 10.1016/j.bbadis.2020.165964 SCOPUS: 85091566236
De Almeida B.P., Vieira A.F., Paredes J., Bettencourt-Dias M., Barbosa-Morais N.L.
Pan-cancer association of a centrosome amplification gene expression signature with genomic alterations and clinical outcome. PLoS Computational Biology15(3):, 2019. [Journal: Article] [CI: 34] [IF: 4,7]
DOI: 10.1371/journal.pcbi.1006832 SCOPUS: 85062866810
Sousa B., Pereira J., Paredes J.
The crosstalk between cell adhesion and cancer metabolism. International Journal of Molecular Sciences20(8):, 2019. [Journal: Review] [CI: 68] [IF: 4,6]
DOI: 10.3390/ijms20081933 SCOPUS: 85065116094
Marteil G., Guerrero A., Vieira A.F., De Almeida B.P., Machado P., Mendonça S., Mesquita M., Villarreal B., Fonseca I., Francia M.E., Dores K., Martins N.P., Jana S.C., Tranfield E.M., Barbosa-Morais N.L., Paredes J., Pellman D., Godinho S.A., Bettencourt-Dias M.
Over-elongation of centrioles in cancer promotes centriole amplification and chromosome missegregation. Nature Communications9(1):, 2018. [Journal: Article] [CI: 92] [IF: 11,9]
DOI: 10.1038/s41467-018-03641-x SCOPUS: 85044538320
Ribeiro A.S., Nobre A.R., Mendes N., Almeida J., Vieira A.F., Sousa B., Carvalho F.A., Monteiro J., Polónia A., Fonseca M., Sanches J.M., Santos N.C., Seruca R., Paredes J.
SRC inhibition prevents P-cadherin mediated signaling and function in basal-like breast cancer cells. Cell communication and signaling : CCS16(1):, 2018. [Journal: Article] [CI: 15] [IF: 5,1]
DOI: 10.1186/s12964-018-0286-2 SCOPUS: 85056432555
Hoop M., Ribeiro A.S., Rösch D., Weinand P., Mendes N., Mushtaq F., Chen X.Z., Shen Y., Pujante C.F., Puigmartí-Luis J., Paredes J., Nelson B.J., Pêgo A.P., Pané S.
Mobile Magnetic Nanocatalysts for Bioorthogonal Targeted Cancer Therapy. Advanced Functional Materials28(25):, 2018. [Journal: Article] [CI: 103] [IF: 15,6]
DOI: 10.1002/adfm.201705920 SCOPUS: 85040698933
Vieira A.F., DIonísio M.R., Gomes M., Cameselle-Teijeiro J.F., Lacerda M., Amendoeira I., Schmitt F., Paredes J.
P-cadherin: A useful biomarker for axillary-based breast cancer decisions in the clinical practice. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc30(5):698-709, 2017. [Journal: Article] [CI: 14] [IF: 6,7]
DOI: 10.1038/modpathol.2016.232 SCOPUS: 85010868663
Tavares S., Vieira A.F., Taubenberger A.V., Araújo M., Martins N.P., Brás-Pereira C., Polónia A., Herbig M., Barreto C., Otto O., Cardoso J., Pereira-Leal J.B., Guck J., Paredes J., Janody F.
Actin stress fiber organization promotes cell stiffening and proliferation of pre-invasive breast cancer cells. Nature Communications8:, 2017. [Journal: Article] [CI: 117] [IF: 12,4]
DOI: 10.1038/ncomms15237 SCOPUS: 85019618841
Polónia A., Pinto R., Cameselle-Teijeiro J.F., Schmitt F.C., Paredes J.
Prognostic value of stromal tumour infiltrating lymphocytes and programmed cell death-ligand 1 expression in breast cancer. Journal of Clinical Pathology70(10):860-867, 2017. [Journal: Article] [CI: 51] [IF: 2,9]
DOI: 10.1136/jclinpath-2016-203990 SCOPUS: 85027245035
Ribeiro A.S., Carvalho F.A., Figueiredo J., Carvalho R., Mestre T., Monteiro J., Guedes A.F., Fonseca M., Sanches J., Seruca R., Santos N.C., Paredes J.
Atomic force microscopy and graph analysis to study the P-cadherin/SFK mechanotransduction signalling in breast cancer cells. Nanoscale8(46):19390-19401, 2016. [Journal: Article] [CI: 15] [IF: 7,4]
DOI: 10.1039/c6nr04465d SCOPUS: 84998881935
Vieira A.F., Paredes J.
P-cadherin and the journey to cancer metastasis. Molecular Cancer14(1):, 2015. [Journal: Review] [CI: 114] [IF: 5,9]
DOI: 10.1186/s12943-015-0448-4 SCOPUS: 84943426968
Ribeiro A.S., Paredes J.
P-cadherin linking breast cancer stem cells and invasion: A promising marker to identify an "intermediate/metastable" EMT state. Frontiers in Oncology4:, 2015. [Journal: Article] [CI: 81]
DOI: 10.3389/fonc.2014.00371 SCOPUS: 85018189090
Vieira A.F., Ribeiro A.S., Dionísio M.R., Sousa B., Nobre A.R., Albergaria A., Santiago-Gómez A., Mendes N., Gerhard R., Schmitt F., Clarke R.B., Paredes J.
P-cadherin signals through the laminin receptor α6β4 integrin to induce stem cell and invasive properties to basal-like breast cancer cells. Oncotarget5(3):679-692, 2014. [Journal: Article] [CI: 46] [IF: 6,4]
DOI: 10.18632/oncotarget.1459 SCOPUS: 84896821980
Sousa B., Ribeiro A.S., Nobre A.R., Lopes N., Martins D., Pinheiro C., Vieira A.F., Albergaria A., Gerhard R., Schmitt F., Baltazar F., Paredes J.
The basal epithelial marker P-cadherin associates with breast cancer cell populations harboring a glycolytic and acid-resistant phenotype. BMC Cancer14(1):, 2014. [Journal: Article] [CI: 24] [IF: 3,4]
DOI: 10.1186/1471-2407-14-734 SCOPUS: 84908094892
Bernardes N., Ribeiro A., Abreu S., Vieira A., Carreto L., Santos M., Seruca R., Paredes J., Fialho A.
High-throughput molecular profiling of a P-cadherin overexpressing breast cancer model reveals new targets for the anti-cancer bacterial protein azurin. International Journal of Biochemistry and Cell Biology50(1):1-9, 2014. [Journal: Article] [CI: 25] [IF: 4]
DOI: 10.1016/j.biocel.2014.01.023 SCOPUS: 84896720191
Albergaria A., Resende C., Nobre A.R., Ribeiro A.S., Sousa B., Machado J.C., Seruca R., Paredes J., Schmitt F.
CCAAT/Enhancer Binding Protein β (C/EBPβ) Isoforms as Transcriptional Regulators of the Pro-Invasive CDH3/P-Cadherin Gene in Human Breast Cancer Cells. PLoS ONE8(2):, 2013. [Journal: Article] [CI: 19] [IF: 3,5]
DOI: 10.1371/journal.pone.0055749 SCOPUS: 84873547668
Ribeiro A.S., Sousa B., Carreto L., Mendes N., Nobre A.R., Ricardo S., Albergaria A., Cameselle-Teijeiro J.F., Gerhard R., Söderberg O., Seruca R., Santos M.A., Schmitt F., Paredes J.
P-cadherin functional role is dependent on E-cadherin cellular context: A proof of concept using the breast cancer model. Journal of Pathology229(5):705-718, 2013. [Journal: Article] [CI: 69] [IF: 7,3]
DOI: 10.1002/path.4143 SCOPUS: 84875054847
Vieira A.F., Ricardo S., Ablett M.P., Dionísio M.R., Mendes N., Albergaria A., Farnie G., Gerhard R., Cameselle-Teijeiro J.F., Seruca R., Schmitt F., Clarke R.B., Paredes J.
P-cadherin is coexpressed with CD44 and CD49f and mediates stem cell properties in basal-like breast cancer. Stem Cells30(5):854-864, 2012. [Journal: Article] [CI: 61] [IF: 7,7]
DOI: 10.1002/stem.1075 SCOPUS: 84860499799
Paredes J., Figueiredo J., Albergaria A., Oliveira P., Carvalho J., Ribeiro A.S., Caldeira J., Costa A.M., Simões-Correia J., Oliveira M.J., Pinheiro H., Pinho S.S., Mateus R., Reis C.A., Leite M., Fernandes M.S., Schmitt F., Carneiro F., Figueiredo C., Oliveira C., Seruca R.
Epithelial E- and P-cadherins: Role and clinical significance in cancer. Biochimica et Biophysica Acta - Reviews on Cancer1826(2):297-311, 2012. [Journal: Review] [CI: 185] [IF: 9]
DOI: 10.1016/j.bbcan.2012.05.002 SCOPUS: 84861800037
Van Der Werf C.S., Wabbersen T.D., Hsiao N., Paredes J., Etchevers H.C., Kroisel P.M., Tibboel D., Babarit C., Schreiber R.A., Hoffenberg E.J., Vekemans M., Zeder S.L., Ceccherini I., Lyonnet S., Ribeiro A.S., Seruca R., Te Meerman G.J., Van Ijzendoorn S.C.D., Shepherd I.T., Verheij J.B.G.M., Hofstra R.M.W.
CLMP is required for intestinal development, and loss-of-function mutations cause congenital short-bowel syndrome. Gastroenterology142(3):453-462.e3, 2012. [Journal: Article] [CI: 45] [IF: 12,8]
DOI: 10.1053/j.gastro.2011.11.038 SCOPUS: 84857636412
Ricardo S., Vieira A.F., Gerhard R., Leitão D., Pinto R., Cameselle-Teijeiro J.F., Milanezi F., Schmitt F., Paredes J.
Breast cancer stem cell markers CD44, CD24 and ALDH1: Expression distribution within intrinsic molecular subtype. Journal of Clinical Pathology64(11):937-944, 2011. [Journal: Article] [CI: 488] [IF: 2,3]
DOI: 10.1136/jcp.2011.090456 SCOPUS: 80054879984
Albergaria A., Ribeiro A.S., Vieira A.F., Sousa B., Nobre A.R., Seruca R., Schmitt F., Paredes J.
P-cadherin role in normal breast development and cancer. International Journal of Developmental Biology55(7-9):811-822, 2011. [Journal: Review] [CI: 65] [IF: 2,8]
DOI: 10.1387/ijdb.113382aa SCOPUS: 82555201366
Ribeiro A.S., Albergaria A., Sousa B., Correia A.L., Bracke M., Seruca R., Schmitt F.C., Paredes J.
Extracellular cleavage and shedding of P-cadherin: A mechanism underlying the invasive behaviour of breast cancer cells. Oncogene29(3):392-402, 2010. [Journal: Article] [CI: 99] [IF: 7,4]
DOI: 10.1038/onc.2009.338 SCOPUS: 75149183984
Albergaria A., Ribeiro A.S., Pinho S., Milanezi F., Carneiro V., Sousa B., Sousa S., Oliveira C., Machado J.C., Seruca R., Paredes J., Schmitt F.
ICI 182,780 induces P-cadherin overexpression in breast cancer cells through chromatin remodelling at the promoter level: A role for C/EBPβ in CDH3 gene activation. Human Molecular Genetics19(13):2554-2566, 2010. [Journal: Article] [CI: 20] [IF: 8,1]
DOI: 10.1093/hmg/ddq134 SCOPUS: 77954172745
Paredes J., Correia A.L., Ribeiro A.S., Albergaria A., Milanezi F., Schmitt F.C.
P-cadherin expression in breast cancer: A review. Breast Cancer Research9(5):, 2007. [Journal: Review] [CI: 98] [IF: 4,4]
DOI: 10.1186/bcr1774 SCOPUS: 40449115153
Van Marck V., Stove C., Van Den Bossche K., Stove V., Paredes J., Vander Haeghen Y., Bracke M.
P-cadherin promotes cell-cell adhesion and counteracts invasion in human melanoma. Cancer Research65(19):8774-8783, 2005. [Journal: Article] [CI: 89] [IF: 7,6]
DOI: 10.1158/0008-5472.CAN-04-4414 SCOPUS: 25644451938
Paredes J., Stove C., Stove V., Milanezi F., Van Marck V., Derycke L., Mareel M., Bracke M., Schmitt F.
P-cadherin is up-regulated by the antiestrogen ICI 182,780 and promotes invasion of human breast cancer cells. Cancer Research64(22):8309-8317, 2004. [Journal: Article] [CI: 62] [IF: 7,7]
DOI: 10.1158/0008-5472.CAN-04-0795 SCOPUS: 8544229187