Where Ideas Grow

Tumour and Microenvironment Interactions

ABOUT

Our group focuses at understanding the role of the tumour microenvironment, particularly of immune cells, adipocytes and extracellular matrix components, on the modulation of cancer cell invasion and metastasis. Conversely, we are also dedicated to understand how cancer cells modulate the microenvironment, subverting death signals, sustaining proliferation and angiogenesis, and escaping the immune surveillance. Ultimately, we foresee translational application by identifying novel targets and designing more efficient therapies.

 

RESEARCH

For an integrative vision, we are developing novel in vitro and in vivo models, using human decellularized extracellular matrices, to build 3D-organotypic assays and orthotopic animal models to tackle the role of the tumour microenvironment in gastrointestinal (MJ Oliveira) and genitourinary and haematological (R Ribeiro) cancers. We previously demonstrated that human macrophages stimulate gastric and colorectal cancer cell motility/migration, proteolysis and invasion, elucidating the associated molecular mechanisms. Stimulation of invasion was induced by a macrophage EGF-like factor, which in turn stimulates cancer cell EGFR and its downstream-interacting partners (c-Src, Akt, Erk1/2, RhoA and MMP activity). Interestingly, anti-inflammatory macrophages are more pro-invasive than their pro-inflammatory counterparts.
Notably, fractionated ionizing radiation (5x2Gy), as used for rectal cancer treatment, modulates macrophages towards a more pro-inflammatory phenotype sustaining, however, their ability to promote cancer cell invasion, challenging the need for the development of adjuvant therapies. With this aim, we constructed IFN-γ-polyelectrolyte multi-layered films (PEMs) as an immunomodulatory-delivery system. These films of alternate layers of Ch/γ-PGA incorporating pro-inflammatory IFN-γ, impaired macrophage differentiation into an anti-inflammatory profile by efficiently enhancing IL-6, reducing IL-10 expression, and impairing their pro-invasive activity.
By analysing periprostatic adipose tissue, we added new insights into the role of adipose tissue in prostate cancer pathophysiology. Noteworthy, we demonstrated a two-way crosstalk between adipose tissue and prostate cancer cells that ultimately favours tumour progression, and where adipokines and tumour factors are key mediators. In agreement, the transcriptomic analysis of periprostatic adipose tissue revealed that obesity modifies gene expression to foster fat mass growth, whereas prostate cancer induces hypercellularity and reduced immunoinflammatory activity. In addition, we presented previously unrecognized findings on adipose stem cells of prostate tissue in humans, providing a mechanistic link between adipose tissue, adipose stem cells and PCa.

Team

Selected Publications

Peirsman A., Blondeel E., Ahmed T., Anckaert J., Audenaert D., Boterberg T., Buzas K., Carragher N., Castellani G., Castro F., Dangles-Marie V., Dawson J., De Tullio P., De Vlieghere E., Dedeyne S., Depypere H., Diosdi A., Dmitriev R.I., Dolznig H., Fischer S., Gespach C., Goossens V., Heino J., Hendrix A., Horvath P., Kunz-Schughart L.A., Maes S., Mangodt C., Mestdagh P., Michlíková S., Oliveira M.J., Pampaloni F., Piccinini F., Pinheiro C., Rahn J., Robbins S.M., Siljamäki E., Steigemann P., Sys G., Takayama S., Tesei A., Tulkens J., Van Waeyenberge M., Vandesompele J., Wagemans G., Weindorfer C., Yigit N., Zablowsky N., Zanoni M., Blondeel P., De Wever O.,
MISpheroID: a knowledgebase and transparency tool for minimum information in spheroid identity. Nature Methods18(11):1294-1303, 2021. [Journal: Article] [CI: 7] [IF: 48]
DOI: 10.1038/s41592-021-01291-4 SCOPUS: 85118431713

Cardoso A.P., Pinto M.L., Castro F., Costa Â.M., Marques-Magalhães Â., Canha-Borges A., Cruz T., Velho S., Oliveira M.J.,
The immunosuppressive and pro-tumor functions of CCL18 at the tumor microenvironment. Cytokine and Growth Factor Reviews60:107-119, 2021. [Journal: Review] [CI: 11] [IF: 17,7]
DOI: 10.1016/j.cytogfr.2021.03.005 SCOPUS: 85104442722

Castro F., Leite Pereira C., Helena Macedo M., Almeida A., José Silveira M., Dias S., Patrícia Cardoso A., José Oliveira M., Sarmento B.,
Advances on colorectal cancer 3D models: The needed translational technology for nanomedicine screening. Advanced Drug Delivery Reviews175:, 2021. [Journal: Review] [CI: 8] [IF: 17,9]
DOI: 10.1016/j.addr.2021.06.001 SCOPUS: 85108070633

Castro F., Pinto M.L., Pereira C.L., Serre K., Barbosa M.A., Vermaelen K., Gärtner F., Gonçalves R.M., De Wever O., Oliveira M.J.,
Chitosan/γ-PGA nanoparticles-based immunotherapy as adjuvant to radiotherapy in breast cancer. Biomaterials257:, 2020. [Journal: Article] [CI: 31] [IF: 12,5]
DOI: 10.1016/j.biomaterials.2020.120218 SCOPUS: 85088642097

Martins F., Oliveira R., Cavadas B., Pinto F., Cardoso A.P., Castro F., Sousa B., Pinto M.L., Silva A.J., Adão D., Loureiro J.P., Pedro N., Reis R.M., Pereira L., Oliveira M.J., Costa A.M.,
Hypoxia and macrophages act in concert towards a beneficial outcome in colon cancer. Cancers12(4):, 2020. [Journal: Article] [CI: 2] [IF: 6,6]
DOI: 10.3390/cancers12040818 SCOPUS: 85082958618

Pinto M.L., Rios E., Durães C., Ribeiro R., Machado J.C., Mantovani A., Barbosa M.A., Carneiro F., Oliveira M.J.,
The two faces of tumor-associated macrophages and their clinical significance in colorectal cancer. Frontiers in Immunology10(AUG):, 2019. [Journal: Article] [CI: 99] [IF: 5,1]
DOI: 10.3389/fimmu.2019.01875 SCOPUS: 85071761383

Castro F., Cardoso A.P., Gonçalves R.M., Serre K., Oliveira M.J.,
Interferon-gamma at the crossroads of tumor immune surveillance or evasion. Frontiers in Immunology9(MAY):, 2018. [Journal: Review] [CI: 483] [IF: 4,7]
DOI: 10.3389/fimmu.2018.00847 SCOPUS: 85046686322

Pinto M.L., Rios E., Silva A.C., Neves S.C., Caires H.R., Pinto A.T., Durães C., Carvalho F.A., Cardoso A.P., Santos N.C., Barrias C.C., Nascimento D.S., Pinto-do-Ó P., Barbosa M.A., Carneiro F., Oliveira M.J.,
Decellularized human colorectal cancer matrices polarize macrophages towards an anti-inflammatory phenotype promoting cancer cell invasion via CCL18. Biomaterials124:211-224, 2017. [Journal: Article] [CI: 78] [IF: 8,8]
DOI: 10.1016/j.biomaterials.2017.02.004 SCOPUS: 85013069713

Teresa Pinto A., Laranjeiro Pinto M., Patrícia Cardoso A., Monteiro C., Teixeira Pinto M., Filipe Maia A., Castro P., Figueira R., Monteiro A., Marques M., Mareel M., Dos Santos S.G., Seruca R., Adolfo Barbosa M., Rocha S., JoséOliveira M.,
Ionizing radiation modulates human macrophages towards a pro-inflammatory phenotype preserving their pro-invasive and pro-angiogenic capacities. Scientific Reports6:, 2016. [Journal: Article] [CI: 104] [IF: 4,3]
DOI: 10.1038/srep18765 SCOPUS: 84954288518

Cardoso A.P., Pinto M.L., Pinto A.T., Oliveira M.I., Pinto M.T., Gonçalves R., Relvas J.B., Figueiredo C., Seruca R., Mantovani A., Mareel M., Barbosa M.A., Oliveira M.J.,
Macrophages stimulate gastric and colorectal cancer invasion through EGFR Y 1086, c-Src, Erk1/2 and Akt phosphorylation and smallGTPase activity. Oncogene33(16):2123-2133, 2014. [Journal: Article] [CI: 84] [IF: 8,5]
DOI: 10.1038/onc.2013.154 SCOPUS: 84899425243

Ongoing Projects

Pré-habilitação para melhorar o tratamento oncológico em doentes com adenocarcinoma da junção gastroesofágica e do estômago
Reference: PTDC/SAU-DES/7945/2020
Proponent: Instituto Português de Oncologia do Porto FG, EPE
Sponsor: FCT - Fundação para a Ciência e a Tecnologia
From 01-JAN-21 to 31-DEC-23
bridging iRon metabolism and immunE cells at the irrAdiateD tumOUr microenvironmenT to identify novel targets for pioneering therapeutic approaches
Reference: EXPL/BIA-CEL/1225/2021
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
diSsect thE tumor microenvironment to battle caNcer radioreSIsTance and Immune eScapE
Reference: PTDC/MED-ONC/4165/2021
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 31-DEC-24
DiSsect thE tumor microenvironment to battle caNcer radioreSIsTance and Immune eScapE
Reference: PESSOA 2022-2023
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: FCT - Fundação para a Ciência e a Tecnologia
From 07-MAR-22 to 07-MAR-23