Tumour and Microenvironment Interactions
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.
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.
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: 63] [IF: 8,5]
DOI: 10.1038/onc.2013.154 SCOPUS: 84899425243. .
Ferreira J.A., Peixoto A., Neves M., Gaiteiro C., Reis C.A., Assaraf Y.G., Santos L.L.,
Mechanisms of cisplatin resistance and targeting of cancer stem cells: Adding glycosylation to the equation. Drug Resistance Updates24:34-54, 2016. [Journal: Article] [CI: 81] [IF: 10,9]
DOI: 10.1016/j.drup.2015.11.003 SCOPUS: 84954133417. .
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: 50] [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: 65] [IF: 4,3]
DOI: 10.1038/srep18765 SCOPUS: 84954288518. .