Targeting Lysyl Oxidase Family Meditated Matrix Cross-Linking as an Anti-Stromal Therapy in Solid Tumours
Congratulations to Kaitlin and Yordanos who just had their co-first author review published inCancers as part of a special edition on Treating the Cancer Matrix: Progress in the Identification of Potential Therapeutic Targets. Also a shout out to Rhiannon for her amazing illustrator skills and creating some beautiful figures. And finally to Jess, who as co-senior author played an instrumental role in bringing everything together.
Remodeling of the extracellular matrix (ECM) in solid tumours. In healthy tissue, the ECM has a structured basement membrane consisting primarily of collagens IV and VI as well as a scaffolding arrangement of fibrillar collagens that are predominantly secreted by the fibroblasts. In comparison, solid tumours typically consist of more densely packed, aberrantly cross-linked fibrillar collagens resulting from the recruitment and activation of CAFs. As the level of deposition of fibrillar collagens such as collagens I, III and V increases in the tumour ECM, so too does LOX family mediated collagen cross-linking. In addition, tumour ECM results in a breakdown of the structure of the normal basement membrane.Continue reading →
Australian Pancreatic Cancer Matrix Atlas (APMA) as a national and international portal for pancreatic cancer and matrix biology research
We are delighted to announce the launch of our Avner Australian Pancreatic Cancer Matrix Atlas (APMA) as a national and international portal for pancreatic cancer and matrix biology research.
About APMA
Desmoplasia (fibrosis) is a key hallmark of pancreatic cancer, which can be targeted in concert with tumour cell-centric therapies. The overarching goal of APMA is to facilitate the translation of stromal-centric therapy as a mainstay in our emerging multimodal armoury against pancreatic cancer.
APMA is a collaborative effort by researchers at the Garvan Institute of Medical Research and The Kinghorn Cancer Centre in Sydney, working closely with clinical teams at Royal North Shore Hospital.
Committee Members
Prof. Paul Timpson, A/Prof. Thomas Cox, A/Prof. Marina Pajic, Prof. Anthony Gill, Dr. Brooke Pereira, Dr. David Herrmann, Prof. Jas Samra, Amber Johns, Gloria Jeong.
Vision and goals
APMA’s aim is to better understand how the dynamic extracellular matrix landscape is linked to alterations in drug response and patient survival in pancreatic cancer. By mapping the histological, immunohistochemical, and proteomic differences between normal pancreatic tissue and matched pancreatic cancer samples we aim to define which matrix elements are deregulated in this disease and reveal new targets.
Detailed comprehensive mapping of the topology and 3D structure of the matrix in native pancreatic tissue and pancreatic cancer, in correlation with clinicopathological and genetic sequencing data, has not been possible until now. The Garvan Institute of Medical Research, working with the Royal North Shore Hospital (RNSH) here in Australia are perfectly placed to achieve this, thereby establishing the first national and international comprehensive human pancreatic cancer matrix database.
APMA is positioned to become an international resource held in Australia for pancreatic cancer matrix targeting, creating a portal for matrix biology researchers and clinicians to interrogate and query disease progression, outcome, survival and relapse in the context of matrix composition and 3D matrix topology. APMA integrates our laboratory based studies of the matrix with clinicopathological data including survival, relapse, and resistance, to identify matrix companion biomarkers and actionable targets that may be diagnostic and/or prognostic.
This is an exciting time for the Matrix and Metastasis team as we have been collaborating closely with Pharmaxis recently in developing a pre-clinical portfolio to help build a case for potentially transitioning this compound through to a clinical trial in pancreatic cancer patients. Pharmaxis is already seeking to progress this compound in the myelofibrosis space, and so working with our team, we are exploring the potential for this exciting anti-fibrotic compound in other cancer settings.
CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer
Working together with A/Prof Paul Timpson’s lab, we are pleased to announce that our recent review on targetting CAFs in pancreatic cancer has just been published in Trends In Cancer.
In this work we explore how different aspects of CAF heterogeneity are defined and how these manifest in multiple cancers, with a focus on pancreatic ductal adenocarcinoma (PDAC).
CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan
We are super excited to announce that our recent work in close collaboration with A/Prof Paul Timpson has just been published in Nature Communications (view the full Open-Access article here)
In this work (which was a large international collaboration), co-led by our team and Paul Timpson’s team (also at the Garvan Institute), we show that remodeling of the stromal tissue in and around pancreatic tumours may be the key to stopping their spread and improving chemotherapy outcomes.
What we did
We already know that tumours are made up of heterogenous populations of cancer cells with different mutational landscapes. Furthermore, recently, the field has begun to realise that the cancer associated fibroblasts (CAFs) present in and around the tumour are also a diverse collection of subpopulations.
The Mini‐Organo: A rapid high‐throughput 3D coculture organotypic assay for oncology screening and drug development
Just published in Cancer Reports is our new protocol paper detailing the development of a rapid high-throughput (96wp) 3D organotypic coculture assay that is optimised for screening cancer cell and cancer-associated fibroblast response to drugs in physiologically relevant matrices.
Cancer Council NSW grants for innovative cancer research
Great news! The Matrix & Metastasis Lab been awarded a three-year project grant from Cancer Council NSW to explore a new combination approach to treating pancreatic cancer.
The project will look at how to target the Lysyl Oxidase (LOX) family of enzymes in in pancreatic cancer with the goal of improving outcomes in patients.
Pancreatic cancer has one of the poorest survival rates of all cancer, with only 25% of people surviving one year after diagnosis and only 8% for five years. This project will look at the tissue in and around pancreatic cancers, which can affect how successful chemotherapy treatment is in a patient.
The aim is to combining biology and engineering to generate 3D models that mimic tumours, along with cutting edge imaging technology and mouse models, to investigate the potential of co-targeting the Lysyl Oxidase family together with already approved cancer drugs to improve patient outcome.
Dr Thomas Cox receiving the award on behalf of the team at CCNSW’s annual Research Awards Evening.
The Matrix and Metastasis group is excited to be welcoming two new Honours students to the team for 2019.
Yordanos Setargew (left) and Shivanjali Ratnaseelan (right) will both be joining us to spend the next 10 months in the lab as part of their UNSW Sydney, School of Medical Sciences (SoMS) Honours Program.
Yordanos will be looking at new ways to target the lysyl oxidase (LOX) family in pancreatic cancer, and Shivanjali will be looking at how the biomechanical properties of the tumour microenvironment alter breast cancer cell sensitivity to chemotherapy.
We’re exited to reveal that we have been working hard with Pharmaxis on the development of their lysyl oxidase (LOX) systemic inhibitor for the potential use as a stromal co-targeting agent in pancreatic cancer.
Pharmaxis has developed an oral drug that inhibits all LOX family members, and which has shown to lead to significant reductions in fibrosis (scarring) in in-vivo models of kidney fibrosis, lung fibrosis, myelofibrosis and now with our help, in models of pancreatic cancer.
Removing physiological motion from intravital and clinical functional imaging data
Galene is a new tool just published in eLife that can correct for physiological motion in live imaging data post-acquisition.
eLife digest
Understanding how molecules and cells behave in living animals can give researchers key insights into what goes wrong in diseases such as cancer, and how well potential treatments for these diseases work. Continue reading →
I’m delighted to announce that Jessica Chitty will shortly be joining the lab as a postdoctoral research fellow. Jessica has just completed her Ph.D at the University of Queensland and is making the move south to join our team.
Having completed a degree in Biochemistry in the UK, and her Ph.D in Australia, Jessica brings experience in investigating the translational repurposing of key anti-cancer/antimycotic targets, along with significant expertise in enzyme biochemistry and molecular biology in the context of rational drug design, focusing towards translational research.
Jessica will focus her work on our ongoing interest into the lysyl oxidase family of enzymes and their role in pancreatic cancer.
Our new paper on short-term pulsed treatment, or ‘priming’ as a treatment strategy to boost chemotherapy has just been published in Science Translational Medicine.
The research, spearheaded by Dr. Paul Timpson and Dr. Marina Pajic here at the Garvan Institute of Medical Research in Sydney, has uncovered a promising new approach to treating pancreatic cancer. By targeting the tissue surrounding the tumour to make it ‘softer’, it leads to tumours being more responsive to chemotherapy.
I’m delighted to announce that Jessica Chitty will shortly be joining the lab as a postdoctoral research fellow. Jessica has just completed her Ph.D at the University of Queensland and is making the move south to join our team.
