Where Ideas Grow

Cytoskeletal Regulation & Cancer


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.



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.


Selected Publications

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: 16] [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: 8] [IF: 4]
DOI: 10.1038/s41598-019-56296-z SCOPUS: 85077305562

Janody F.,
The Big Bang of tissue growth: Apical cell constriction turns into tissue expansion. Journal of Cell Biology217(3):807-808, 2018. [Journal: Note] [IF: 8,9]
DOI: 10.1083/jcb.201801076 SCOPUS: 85042848294

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: 84] [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

Gaspar P., Holder M.V., Aerne B.L., Janody F., Tapon N.,
Zyxin antagonizes the FERM protein expanded to couple f-actin and yorkie-dependent organ growth. Current Biology25(6):679-689, 2015. [Journal: Article] [CI: 47] [IF: 9]
DOI: 10.1016/j.cub.2015.01.010 SCOPUS: 84926322744

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: 13] [IF: 6,1]
DOI: 10.1242/dev.113340 SCOPUS: 84926380808

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: 22] [IF: 6]
DOI: 10.1093/hmg/ddv312 SCOPUS: 84943762566

Fernández B.G., Jezowska B., Janody F.,
Drosophila actin-Capping Protein limits JNK activation by the src proto-oncogene. Oncogene33(16):2027-2039, 2014. [Journal: Article] [CI: 27] [IF: 8,5]
DOI: 10.1038/onc.2013.155 SCOPUS: 84899417132

Amândio A.R., Gaspar P., Whited J.L., Janody F.,
Subunits of the Drosophila actin-capping protein heterodimer regulate each other at multiple levels. PLoS ONE9(5):, 2014. [Journal: Article] [CI: 11] [IF: 3,2]
DOI: 10.1371/journal.pone.0096326 SCOPUS: 84900398117

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
Protein REcycling SuStaINs Triple Negative Breast Cancer aGgressiveness
Reference: Projeto 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