ARTICLE: Matrix stiffness induces Epithelial-Mesenchymal transition and promotes chemoresistance in pancreatic cancer cells

Our latest paper, published in Oncogenesis. 

Increased matrix rigidity associated with the fibrotic reaction is documented to stimulate intracellular signalling pathways that promote cancer cell survival and tumour growth. Pancreatic cancer is one of the stiffest of all human solid carcinomas and is characterised by a remarkable desmoplastic reaction. Here, we use mouse models genetically engineered to recapitulate human pancreatic cancer, and several pancreatic cancer cell lines as a model, to investigate the effect of matrix stiffness in epithelial-mesenchymal transition (EMT) and resistance to chemotherapeutics. We found that recapitulation of the fibrotic rigidities found in pancreatic cancer tissues promote elements of EMT including increases in vimentin expression, decreases in E-cadherin expression, nuclear localisation of β-catenin, YAP, and TAZ, and changes in cell shape towards a mesenchymal phenotype. We also report that stiffness induces chemoresistance to paclitaxel, but not to gemcitabine, both commonly used therapeutics, suggesting that environmental rigidity underlies an aspect of chemoresistance.

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ARTICLE: Substrate Rigidity Controls Activation and Durotaxis in Pancreatic Stellate Cells

Our latest paper, published in Scientific Reports. Read it here.

Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive malignancy characterised by the presence of extensive desmoplasia, thought to be responsible for the poor response of patients to systemic therapies. Pancreatic stellate cells (PSCs) are key mediators in the production of this fibrotic stroma, upon activation transitioning to a myofibroblast-like, high matrix secreting phenotype. Given their importance in disease progression, characterisation of PSC activation has been extensive, however one aspect that has been overlooked is the mechano-sensing properties of the cell. Here, through the use of a physiomimetic system that recapitulates the mechanical microenvironment found within healthy and fibrotic pancreas, we demonstrate that matrix stiffness regulates activation and mechanotaxis in PSCs. We show the ability of PSCs to undergo phenotypic transition solely as a result of changes in extracellular matrix stiffness, whilst observing the ability of PSCs to durotactically respond to stiffness variations within their local environment. Our findings implicate the mechanical microenvironment as a potent contributor to PDAC progression and survival via induction of PSC activation and fibrosis, suggesting that direct mechanical reprogramming of PSCs may be a viable alternative in the treatment of this lethal disease.

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ARTICLE: Cross-linking of a biopolymer-peptide co-assembly system

Molecular self-assembly is widely used for the fabrication of complex functional biomaterials to replace and/or repair any tissue or organ in the body. However, maintaining the stability and corresponding functionality of these kinds of materials in physiological conditions remains a challenge. Chemical cross-linking strategies (natural or synthetic) have been used in an effort to improve their structural integrity. Here we investigate key performance parameters of different cross-linking strategies for stabilising self-assembled materials with potential biomedical applications using a novel protein-peptide co-assembling membrane as proof-of-concept. From the different cross-linkers tested, the natural cross-linker genipin exhibited the best performance. This cross-linker successfully enhanced the mechanical properties of the system enabling the maintenance of the structure in physiological conditions without compromising its bioactivity and biocompatibility. Altogether, we provide a systematic characterization of cross-linking alternatives for self-assembling materials focused on biocompatibility and stability and demonstrate that genipin is a promising alternative for the cross-linking of such materials with a wide variety of potential applications such as in tissue engineering and drug delivery.

Find the full article here.

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Gordon Research Conference, Texas

CMBL leader, Armando del Rio Hernandez, was a keynote speaker and discussion leader at the Gordon Research Conference - Physical Science of Cancer - that took place this week at the Hotel Galvez in Texas.

Talk: Pancreatic cancer, mechanobiology and vitamin A

Chaired session: Cancer Physics in Adhesive Signals and Cell Fate

 

Gordon Research Conferences are prestigious international scientific conferences that have been covering frontier nresearch across a variety of fields for almost a century

https://www.grc.org/programs.aspx?id=17378

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ARTICLE: Adhesive ligand tether length affects the size and length of focal adhesions and influences cell spreading and attachment

Our latest article, published in Scientific Reports. Read it here.

In this paper we have demonstrated how the behaviour of cells can be controlled by carefully altering the length the linkers that attaches them to the surface which they are plated on. The response of cells to physical changes in their surroundings, notably stiffness changes, is well-documented, and important to a wide range of fields from cancer biology to tissue engineering. Up until now, taking advantage of this cellular response has required the use of complex gels to mimic wide ranges of stiffness. Our technique, by contrast, provides a simple alternative that involves coating the surface you wish to use with specific length of attachment linker that tricks the cell into thinking it is on a softer surface. The potential uses of this technique range from practical uses to mechanistic insights: in tissue engineering this process could be used to change the properties of the scaffold into which cells are seeded, directing their fate in the desired manner; in cancer biology, the precise control that the technique gives us over the cell’s environment allows for detailed investigations into what drives metastasis.

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Antonios wins EIT Gold Fellowship

Oxford – CMBL's Antonios CHronopoulos won the gold fellowship award from the 2016 European Institute of Innovation and Technology student competition to develop ExoSonic – a joint project with Tyler Lieberthal aimed at the fabrication of a microfluidic device for early detection of pancreatic cancer.

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ARTICLE: Our research on cancer biophysics uncovers the biomechanical mechanism by which vitamin A inhibits the invasion of pancreatic cancer cells

Our latest article, published in Nature Communications. Read it here.

Pancreatic cancer is associated with advanced fibrosis, which is dense tissue that supports tumour growth, contributes to metastasis and hampers chemotherapy delivery. This fibrosis in pancreatic cancer is driven by pancreatic stellate cells (PSCs), which in this disease are activated and deficient in vitamin A as opposed to their healthy counterparts that reside in normal pancreas and have abundant droplets of vitamin A storage in their cytoplasm. Activated PSCs have a robust cytoskeleton which applies forces on the surrounding to stiffen the tissue and remodel the microenvironment of the tumour to make it favourable for cancer cell invasion.

Our research shows that restoring the vitamin A levels in these cells reprograms them to a quiescent stage similar to the one observed in healthy tissues. This suppresses actomyosin contraction, mechanosensing and force-mediated matrix remodelling and stiffening, which, in turn, creates a microenvironment unfavourable for invasion by pancreatic cancer cells. The reduced invasive behaviour of cancer cells was independent of paracrine signalling between PSCs and cancer cells, and was mostly attributed to the altered biomechanical and/or topographical characteristics of the remodelled microenvironment promoted by ATRA (vitamin A precursor)treatment on PSCs.

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Precision Medicines Conference, 2016: strong showing from CMBL

The latest Precision Medicianes Conference at Imperial College took place on the 14th-15th July, 2016, and was dedicated to Engineering Solutions for Cancer. The CMBL group took a large part in proceedings, providing two talks and three posters for the conference. Particular congratulations to Antonios for winning the Best Poster Award.

Invited talk: Armando del Rio Hernandez, Switching off the forces that drive pancreatic cancer

Talk: Antonios Chronopoulos, Exosonic - a microfluidic device for purification and detection of tumour exosomes for early detection of cancer

Poster presentations:

Antonios Chronopoulos, Exosonic - a microfluidic device for purification and detection of tumour exosomes for early detection of cancer, Winner - Best Poster Award

Dariusz Lachowski, Assaying the rigidity guided migration of Human Tumour Stromal Myofibroblasts (TSM) on polyacrylamide substrates mimicking healthy and fibrotic tissue transition boundary

Alistair Rice, Traction force microscopy with elastic pillars for quantification of forces during cell apoptosis

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International Liver Congress 2016

Dariusz Lachowski from the CMBL group participated in The International Liver Congress in Barcelona, Spain. He was awarded with the Young Investigator bursary and his work was selected within the 5 best posters in the fibrosis category. Dariusz investigates novel biomechanical mechanisms to target liver fibrosis and cancer. 13-17th April 2016, Barcelona, Spain.

http://ilc-congress.eu/

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ExoSonic wins Audience Choice Award

Tyler and Antonis won the Audience Choice award at the 2016 Institute of Global Health Innovation Student Competition Dragon's Den event for their ExoSonic technology. Entries to this competition were evaluated based on technical/clinical/business innovation, potential global health impact, and plans for economic implementation and feasibility.

 

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