Where Ideas Grow

Cytoskeletal Regulation & Cancer

ABOUT

Our main objective is to shed light on how the organisation, dynamics and mechanical properties of the cytoskeleton spatially coordinate the whole interconnected cancer signalling network to drive emergent cellular responses.

 

RESEARCH

Cancer evolution is a long-lasting process that involves multiple steps, going from benign conditions to pre-malignant lesions, until these harmless conditions are converted into aggressive malignancies by additional events. Not all pre-cancerous lesions will actually evolve to aggressive cancer. Those that will not may never become clinically relevant. Yet, the actual risk that a pre-cancerous condition will progress to an overt malignancy remains unknown. Those that progress will acquire invading and metastatic potential. These processes, in addition to intrinsic or acquired cytotoxic drug resistance, are responsible for the majority of death in cancer patients. This is particularly true for triple-negative breast cancer (TNBC), which remains the most lethal subtype of breast cancer. Still, the underlying mechanisms remain poorly understood.

Cancer initiation and progression depends on cell-autonomous signalling pathways. These pathways are known to affect the cytoskeleton in order to best adapt cell geometry and mechanics to particular cancer cell behaviours. However, this regulatory link is not unidirectional. Our team contributed to unveil mechanisms by which the cytoskeleton governs the location, duration, and intensity of cancer signalling pathways activation through diverse mechanisms, ranging from force generation to the spatial distribution of signalling regulators [2017 Nat. Comm.; 2019-Sci. Rep.; 2023-DMM]. Altogether, our observations suggest that global and/or local changes in the organization, dynamics and mechanical properties of the cytoskeleton affect many signalling molecules simultaneously within the whole interconnected signalling network. With the ultimate goal to define the downstream cytoskeleton-dependent cancer signalling network, we turned to computational modelling of large biological networks, which capture the complexity of signalling crosstalk and feedbacks and can generate powerful hypotheses [2020 Can. Res.; 2021-IJMS].

Building up on our findings, we are currently using multi-disciplinary approaches, combining experimental models (Drosophila melanogaster, inducible mammalian epithelial cell models, TNBC patient-derived organoids) and computational modelling to answer four specific questions: How cell shape, a direct readout of intrinsic forces exerted by the cytoskeleton on the cell membrane, constrains the signalling network to predispose for or to hamper tumour initiation? How cytoskeleton-adhesions scaffolds orchestrate the signalling network instructing benign lesions to progress to malignant cancer cells? How the cytoskeleton and forces by the extracellular matrix propel TNBC cell invasion? How cytoskeleton-adhesions scaffolds supervise chemoresistant signalling networks in TNBC?

We expect to shed light into the rationale behind cancer signalling network. This knowledge should guide our awareness on mechanisms by which the transcriptional programme is supervised by cell architecture to control cell fate decision during normal and disease development. Importantly, it may ultimately translate into tools that are relevant for the therapeutic intervention of cancer.

In situ proximity ligation assay for E-cadherin and p120ctn (red) in MCF10A-ER-Src cells stained with Phalloidin to mark actin filaments (green) and DAPI (blue), which stain the nucleus.

Team

Selected Publications

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: 3] [IF: 4,3 (*)]
DOI: 10.1242/dmm.049652 SCOPUS: 85150628415

Oliveira A.C., Santos M., Pinho M., Lopes C.S.,
String/Cdc25 phosphatase is a suppressor of Tau-associated neurodegeneration. DMM Disease Models and Mechanisms16(1):, 2023. [Journal: Article] [IF: 4,3 (*)]
DOI: 10.1242/dmm.049693 SCOPUS: 85147045472

Sluimer L.M., Bullock E., Rätze M.A.K., Enserink L., Overbeeke C., Hornsveld M., Brunton V.G., Derksen P.W.B., Tavares S.,
SKOR1 mediates FER kinase-dependent invasive growth of breast cancer cells. Journal of Cell Science136(3):, 2023. [Journal: Article] [CI: 2] [IF: 4,0 (*)]
DOI: 10.1242/jcs.260243 SCOPUS: 85147458206

Khalil K., Eon A., Janody F.,
Cell Architecture-Dependent Constraints: Critical Safeguards to Carcinogenesis. International Journal of Molecular Sciences23(15):, 2022. [Journal: Review] [CI: 1] [IF: 5,6]
DOI: 10.3390/ijms23158622 SCOPUS: 85136340509

Selvaggio G., Chaouiya C., Janody F.,
In silico logical modelling to uncover cooperative interactions in cancer. International Journal of Molecular Sciences22(9):, 2021. [Journal: Review] [CI: 1] [IF: 6,2]
DOI: 10.3390/ijms22094897 SCOPUS: 85105132637

Selvaggio G., Canato S., Pawar A., Monteiro P.T., Guerreiro P.S., Manuela Brás M., Janody F., Chaouiya C.,
Hybrid epithelial–mesenchymal phenotypes are controlled by microenvironmental factors. Cancer Research80(11):2407-2420, 2020. [Journal: Article] [CI: 29] [IF: 12,7]
DOI: 10.1158/0008-5472.CAN-19-3147 SCOPUS: 85085904168

Jain P.B., Guerreiro P.S., Canato S., Janody F.,
The spectraplakin Dystonin antagonizes YAP activity and suppresses tumourigenesis. Scientific Reports9(1):, 2019. [Journal: Article] [CI: 12] [IF: 4]
DOI: 10.1038/s41598-019-56296-z SCOPUS: 85077305562

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: 107] [IF: 12,4]
DOI: 10.1038/ncomms15237 SCOPUS: 85019618841

Brás-Pereira C., Potier D., Jacobs J., Aerts S., Casares F., Janody F.,
dachshund Potentiates Hedgehog Signaling during Drosophila Retinogenesis. PLoS Genetics12(7):, 2016. [Journal: Article] [CI: 11] [IF: 6,1]
DOI: 10.1371/journal.pgen.1006204 SCOPUS: 84982854129

Brás-Pereira C., Casares F., Janody F.,
The retinal determination gene dachshund restricts cell proliferation by limiting the activity of the Homothorax-Yorkie complex. Development142(8):1470-1479, 2015. [Journal: Article] [CI: 14] [IF: 6,1]
DOI: 10.1242/dev.113340 SCOPUS: 84926380808

Ongoing Projects

COoperative Mechanical couPling of adherens junctions and focaL adhesIons supporting progression to invasive breast CancEr
Reference: PTDC/BIA-BFS/0812/2021
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
Medalhas de Honra L’Oréal Portugal para as Mulheres na Ciência 2021
Reference: Premio L?Oreal Portugal 2021 - S.Tavares
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: Sandra Raquel Oliveira Tavares
From 01-APR-22 to 31-DEC-24
Protein REcycling SuStaINs Triple Negative Breast Cancer aGgressiveness
Reference: Gilead GENESE 2022 - Proj. 17773 - PO 205013391
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: Gilead Sciences
From 01-JAN-23 to 31-DEC-24
Identificação dos componentes de reciclagem proteica que controlam a formação de metástases
Reference: Premio Bial - Maria de Sousa 2022 - n?8/2022
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: Fundação Bial
From 02-JAN-23 to 31-DEC-24