Where Ideas Grow

Epithelial Interactions in Cancer

Note: It is with deep sadness that we inform of the passing of Professor Raquel Seruca on May 30th, 2022. For research inquiries, please contact Joana Figueiredo (jfigueiredo@ipatimup.pt) or Sérgia Velho (svelho@ipatimup.pt).

 

ABOUT

The long-term goal of the EPIC (EPithelial Interactions in Cancer) group is to uncover how epithelial cancer cells interact with each other or with other cells of the tumour microenvironment, impacting cancer cell invasion, migration, and metastasis, as well as resistance to therapy. Specifically, and based on two common epithelial-derived cancers (gastric and colorectal), the group aims to establish the contribution of adhesion molecules and oncogenic signalling to cancer development, addressing the ability of cancer cells to sense, adapt and modulate the tumour microenvironment.
EPIC researchers have expertise in adhesion and cancer-associated pathways involving host cellular and non-cellular interactions within the tumour tissue. The group encompasses skills on molecular and cell biology, pathology, and oncology. Furthermore, it has available unique biological reagents that include stable cell lines expressing wild-type and mutant forms of a major adhesion molecule (E-cadherin), series of primary tumours and several in vitro and in vivo experimental models.

The group is structured in two working teams, addressing complementary research topics. FIGUEIREDO’s team aims at identifying key molecules and signalling networks mediated by E-cadherin dysfunction in cancer. VELHO´s team aims at dissecting the role of oncogenic signalling in the interaction of cancer cells with the tumour microenvironment and how it impacts cancer tissue remodelling and resistance to therapy.

The accomplishment of these research goals will contribute to the development of new tools for patient surveillance, as well as to the design and improvement of therapeutic strategies targeting cancer cell invasion and metastasis.
 

 

 

RESEARCH

FIGUEIREDO’S team has been focused on the functional consequences of E-cadherin loss in epithelial architecture and consequent cell invasive behaviour. We have identified distinct trafficking-related partners and novel mechanisms that hamper E-cadherin translation, folding and deliver to the basolateral membrane, impairing cell adhesion and increasing cell invasive potential. Currently, we aim to identify critical moieties and signalling pathways that are associated with a specific mechanotransduction program involving a remodelling of cell-ECM interactions, cytoskeletal reorganization and cell reshaping. Of note, using our knowledge on cell biology of adhesion molecules, we provide services worldwide on functional assays of E-cadherin missense mutations found within the frame of International Gastric Cancer Linkage Consortium.

VELHO’s team is focused on the role of oncogenic signalling in orchestrating the crosstalk between colorectal cancer cells and the tumour microenvironment, and how it impacts tumour initiation, progression and resistance to therapy. By identifying the regulators of this crosstalk and the routes of communication, we expect to uncover novel treatment strategies targeting the interaction of cancer cells with the microenvironment. Previous work from our team supports a role for mutant KRAS in mediating cancer cell interaction with microenvironment factors, either by regulating cancer cells´ response to external factors or by promoting a pro-tumorigenic microenvironment. In particular, we have found that, by regulating clinically relevant molecules involved in the communication with the microenvironment, KRAS mutant colorectal cancer cells impact cancer cell invasion, stemness, and immune escape when challenged with microenvironmental-derived factors. Additionally, by affecting the properties of cancer-associated fibroblasts, KRAS mutant colorectal cancer cells are likely to impact cancer tissue remodelling. Our data is also highlighting the crucial contribution of the tumour microenvironment and 3D chromatin conformation on the regulation of tolerance and resistance to KRAS inhibition. Our team applies in vivo and in vitro studies such as genetically engineered mouse models, 2D and 3D cell culture systems, including patient- and mouse-derived organoids, to answer clinically relevant questions.
 

Targeted knockdown of Drosophila Epithelial-cadherin (green), in the posterior compartment of the wing imaginal disc, results in invasion of wiltype tissues, ectopic Laminin expression (red) and MMP upregulation (blue). This is only observed at the interface with Drosophila Epithelial-cadherin expre

Team

Selected Publications

Figueiredo J., Ferreira R.M., Xu H., Gonçalves M., Barros-Carvalho A., Cravo J., Maia A.F., Carneiro P., Figueiredo C., Smith M.L., Stamenovic D., Morais-de-Sá E., Seruca R.,
Integrin ß1 orchestrates the abnormal cell-matrix attachment and invasive behaviour of E-cadherin dysfunctional cells. Gastric Cancer25(1):124-137, 2022. [Journal: Article] [CI: 13] [IF: 7,4]
DOI: 10.1007/s10120-021-01239-9 SCOPUS: 85114350265

Dias Carvalho P., Mendonça S., Martins F., Oliveira M.J., Velho S.,
Modulation of Fibroblast Phenotype by Colorectal Cancer Cell-Secreted Factors Is Mostly Independent of Oncogenic KRAS. Cells11(16):, 2022. [Journal: Article] [CI: 1] [IF: 6]
DOI: 10.3390/cells11162490 SCOPUS: 85137125241

Dias Carvalho P., Martins F., Mendonça S., Ribeiro A., Machado A.L., Carvalho J., Oliveira M.J., Velho S.,
Mutant KRAS modulates colorectal cancer cells invasive response to fibroblast-secreted factors through the HGF/C-MET axis. International Journal of Cancer151(10):1810-1823, 2022. [Journal: Article] [CI: 2] [IF: 6,4]
DOI: 10.1002/ijc.34225 SCOPUS: 85135637132

Carvalho P.D., Martins F., Carvalho J., Oliveira M.J., Velho S.,
Mutant KRAS-Associated Proteome Is Mainly Controlled by Exogenous Factors. Cells11(13):, 2022. [Journal: Article] [CI: 1] [IF: 6]
DOI: 10.3390/cells11131988 SCOPUS: 85132292190

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: 216] [IF: 41,3]
DOI: 10.1016/S1470-2045(20)30219-9 SCOPUS: 85088930288

Carvalho P.D., Machado A.L., Martins F., Seruca R., Velho S.,
Targeting the tumor microenvironment: An unexplored strategy for mutant KRAS tumors. Cancers11(12):, 2019. [Journal: Review] [CI: 31] [IF: 6,1]
DOI: 10.3390/cancers11122010 SCOPUS: 85077305268

Figueiredo J., Melo S., Gamet K., Godwin T., Seixas S., Sanches J.M., Guilford P., Seruca R.,
E-cadherin signal sequence disruption: A novel mechanism underlying hereditary cancer. Molecular Cancer17(1):, 2018. [Journal: Letter] [CI: 11] [IF: 10,7]
DOI: 10.1186/s12943-018-0859-0 SCOPUS: 85051027654

Carvalho P.D., Guimarães C.F., Cardoso A.P., Mendonça S., Costa Â.M., Oliveira M.J., Velho S.,
KRAS oncogenic signaling extends beyond cancer cells to orchestrate the microenvironment. Cancer Research78(1):7-14, 2018. [Journal: Review] [CI: 120] [IF: 8,4]
DOI: 10.1158/0008-5472.CAN-17-2084 SCOPUS: 85040196244

Oliveira C., Pinheiro H., Figueiredo J., Seruca R., Carneiro F.,
Familial gastric cancer: Genetic susceptibility, pathology, and implications for management. The Lancet Oncology16(2):e60-e70, 2015. [Journal: Review] [CI: 277] [IF: 26,5]
DOI: 10.1016/S1470-2045(14)71016-2 SCOPUS: 84921774175

Caldeira J., Figueiredo J., Brás-Pereira C., Carneiro P., Moreira A.M., Pinto M.T., Relvas J.B., Carneiro F., Barbosa M., Casares F., Janody F., Seruca R.,
E-cadherin-defective gastric cancer cells depend on Laminin to survive and invade. Human Molecular Genetics24(20):5891-5900, 2015. [Journal: Article] [CI: 28] [IF: 6]
DOI: 10.1093/hmg/ddv312 SCOPUS: 84943762566

Ongoing Projects

Deconstructing the Cell Communication Routes of mutant KRAS Colorectal Liver to Lung Metastasis: improving patient survival
Reference: 2022.05346.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
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
Nuclear biomarkers for predictive prognosis of hereditary diffuse gastric cancer.
Reference: NICE
Proponent: Ipatimup
Sponsor: No Stomach for Cancer, Inc
From 01-MAR-21 to 31-JAN-25