Summary
During my graduated studies, my research focused on elucidating signalling pathways to reprogram the tumour microenvironment in pancreatic and liver cancers. These projects identified two molecular mechanisms by which the retinoic acid receptor beta (RAR-beta) and G protein coupled estrogen receptor (GPER) act as fundamental targets to regulate the activation of the main resident cells in the tumour microenvironment, myofibroblasts. We used all trans-retinoic acid (ATRA) and tamoxifen to target RAR-beta and GPER, respectively. In both cases, myofibroblasts were reprogrammed and their tumour promoting capacities were inhibited.
ATRA and tamoxifen have well-established records in clinics, and have been used to treat leukaemia and breast cancer, respectively. These results open the possibility of repositioning ATRA and tamoxifen as stromal therapies for pancreatic and liver cancers, and possibly other solid tumours. ATRA is undergoing phase II clinical trials in pancreatic cancer patients in the UK. The importance of the pre-clinical discovery that ATRA and tamoxifen can act as novel microenvironmental-targeted therapies is that by redeploying these already approved drugs for the treatment of cancer will bypass the lengthy and costly testing associated with de novo drug discovery.
More recently, I collaborated in a project that identified syndecan-4 as a new mechanosensor that triggers a mechano-signalling cascade, controlling cell mechanics and the synergy between the two big families of cell- extracellular matrix adhesion receptors, integrins and syndecans. Syndecan-4 is a proteoglycan ubiquitously expressed in cells and is implicated in ECM organization. Thus, our findings should impact the fields of tumour stroma remodelling and pathological fibrosis. My contribution to this project: Cell biology work and experiments with permanent magnets, identification of integrin activation in basal membrane upon syndecans-4 mediated force application in the apical side, experiments to identify transmission of mechanical stimuli via syndecans-4/alpha-actinin/actin cytoskeleton. This work was published in Nature Materials in 2020 (PMID: 31907416) and was accompanied by a New and Views article in the same journal. I helped to prepare the summary video to explain our research in layman terms: https://www.youtube.com/watch?feature=youtu.be&v=XPVdx7_V-nU
Finally, I contributed to a project that investigated the effect of matrix stiffness in plasma membrane mechanosensing in liver myofibroblasts. The results of this project were included in an article recently accepted for publication in ACS Nano 2022. We found that substrate stiffness positively regulates plasma membrane tension through a β1 integrin and RhoA-dependent mechanism, which in turns promotes caveolae formation and vesicle exocytosis via Caveolin-1. The membrane tension-dependent regulation of vesicular transport is likely to affect the secretion rate of other proteins and cytokines, promoting paracrine and autocrine signalling in fibrosis, inflammation and cancer.
Selected Publications
Journal Articles
Lachowski D, Matellan C, Gopal S, et al., 2022, Substrate stiffness-driven membrane tension modulates vesicular trafficking via caveolin-1., ACS Nano, Vol:16, ISSN:1936-0851, Pages:4322-4337
Lachowski D, Cortes Lopez J, Matellan C, et al., 2020, G protein-coupled estrogen receptor regulates actin cytoskeleton dynamics to impair cell polarization, Frontiers in Cell and Developmental Biology, Vol:8, ISSN:2296-634X
Chronopoulos A, Thorpe SD, Cortes E, et al., 2020, Syndecan-4 tunes cell mechanics by activating the kindlin-integrin-RhoA pathway, Nature Materials, Vol:19, ISSN:1476-1122, Pages:669-678
Rice A, Cortes Lopez JE, Lachowski D, et al., 2020, GPER activation inhibits cancer cell mechanotransduction and basement membrane invasion via RhoA, Cancers, Vol:12, ISSN:2072-6694
Lachowski D, Cortes E, Rice A, et al., 2019, Matrix stiffness modulates the activity of MMP-9 and TIMP-1 in hepatic stellate cells to perpetuate fibrosis, Scientific Reports, Vol:9, ISSN:2045-2322
Cortes E, Lachowski D, Rice A, et al., 2019, Retinoic acid receptor-β is downregulated in hepatocellular carcinoma and cirrhosis and its expression inhibits myosin-driven activation and durotaxis in hepatic stellate cells, Hepatology, Vol:69, ISSN:0270-9139, Pages:785-802
Cortes E, Lachowski D, Robinson B, et al., 2019, Tamoxifen mechanically reprograms the tumor microenvironment via HIF-1A and reduces cancer cell survival, EMBO Reports, Vol:20, ISSN:1469-221X
Cortes E, Sarper M, Robinson B, et al., 2019, GPER is a mechanoregulator of pancreatic stellate cells and the tumor microenvironment, EMBO Reports, Vol:20, ISSN:1469-221X
Cortes E, Lachowski D, Rice A, et al., 2018, Tamoxifen mechanically deactivates hepatic stellate cells via the G protein-coupled estrogen receptor, Oncogene, Vol:38, ISSN:0950-9232, Pages:2910-2922
Haining AWM, Rahikainen R, Cortes E, et al., 2018, Mechanotransduction in talin through the interaction of the R8 domain with DLC1, PLOS Biology, Vol:16, ISSN:1544-9173, Pages:1-20
Lachowski D, Cortes E, Robinson B, et al., 2018, FAK controls the mechanical activation of YAP, a transcriptional regulator required for durotaxis, The FASEB Journal, Vol:32, ISSN:0892-6638, Pages:1099-1107
Rice AJ, Cortes E, Lachowski D, et al., 2017, Matrix stiffness induces epithelial-mesenchymal transition and promotes chemoresistance in pancreatic cancer cells, Oncogenesis, Vol:6, ISSN:2157-9024, Pages:e352-e352
Lachowski D, Cortes E, Pink D, et al., 2017, Substrate rigidity controls activation and durotaxis in pancreatic stellate cells, Scientific Reports, Vol:7, ISSN:2045-2322
Lachowski D, Cortes E, Robinson BK, et al., 2016, Assaying the rigidity guided migration of human tumour stromal myofibroblasts (TSMs) on polyacrylamide substrates mimicking the healthy and fibrotic tissue transition boundary, Convergent Science Physical Oncology, Vol:2, Pages:044502-044502
Attwood S, Cortes E, Haining, et al., 2016, Adhesive ligand tether length affects the size and length of focal adhesions and influences cell spreading and attachment, Scientific Reports, Vol:6, ISSN:2045-2322
Chronopoulos A, Robinson B, Sarper M, et al., 2016, ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion, Nature Communications, Vol:7, ISSN:2041-1723, Pages:1-12
Sarper M, Cortes E, Lieberthal T, et al., 2016, ATRA modulates mechanical activation of TGF-β by pancreatic stellate cells, Scientific Reports, Vol:6, ISSN:2045-2322
Robinson BK, Cortes E, Rice AJ, et al., 2016, Quantitative analysis of 3D extracellular matrix remodelling bypancreatic stellate cells, Biology Open, Vol:5, ISSN:2046-6390, Pages:875-882
Chapters
Ghose R, Rice AJ, Cortes E, et al., 2020, Implementation of a basement membrane invasion assay using mesenteric tissue, CELL-DERIVED MATRICES, PT B, Editor(s): Caballero, Kundu, Reis, ACADEMIC PRESS LTD-ELSEVIER SCIENCE LTD, Pages:99-122
Conference
Lachowski D, Cortes E, Robinson B, et al., 2016, SAT-402 - Elucidating the Biomechanical Response of Human Hepatic Stellate Cells on Substrates Mimicking Healthy and Fibrotic Matrix Rigidity, EASL International Liver Congress, Elsevier, Pages:S706-S706, ISSN:0168-8278