Matrix and Metastasis

MATRIX AND METASTASIS

Targetting the Extracellular Matrix in Cancer Metastasis

Homeostasis of the extracellular matrix (ECM) is critical for correct organ and tissue function. Both the biochemical and biomechanical properties of the ECM contribute to modulating the behaviour of resident cells and are more than just passive bystanders. In tissue diseases such as cancer, the ECM undergoes significant change. These changes, driven by resident tumour cells, feed into the pathological progression of the disease. Understanding how the changing ECM facilitates tumour progression is an important step in the treatment and prevention of cancer.

Our research focuses on how ECM remodelling influences cancer progression, therapy response, and metastatic dissemination in solid tumours. Specifically we have shown that changes in the ECM are critical in modulating Src, FAK and Akt phosphorylation/activation, VEGF-driven angiogenesis, and nFATc1-mediated osteoclastogenesis.

Over the years we have shown the importance of aberrant ECM remodelling in cancer, including the role in ER-negative breast cancer bone metastasis through the generation of pre-metastatic niches; the importance of LOX and LOX activity in organ fibrosis, and how this enhances metastatic colonisation of cancer cells in these tissues; and how ECM remodelling and not only drives primary tumour growth, but can be used to stratify patients that will respond favourably to treatment with already approved clinical drugs, including bisphosphonates, and Src, Akt, VEGF and FAK inhibitors.

Altogether, our studies have contributed to increasing the current knowledge and understanding of the importance, and targeting potential, of lysyl oxidases, and ECM remodelling in cancer progression and metastasis. Several challenges still lie ahead, yet in the not-too distant future, our aim is to establish targeting of the extracellular matrix as a viable therapeutic approach in the treatment of solid cancers.

Selected Publications

A full up-to-date list of publications is available at www.matrixandmetastasis.com/publications

Last updated: July 2019
(*Equal Contribution / #Corresponding Author)


2019

CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan
Vennin C, Mélénec P, Rouet R, Nobis M, Cazet A, Murphy K, Herrmann D, Reed D, Lucas M, Warren S, Elgundi Z, Pinese M, Kalna G, Roden D, Samuel M, Zaratzian A, Grey S, Da Silva A, Leung W, (APGI) Australian Pancreatic cancer Genome Initiative, Mathivanan S, Wang Y, Braithwaite A, Christ D, Benda A, Parkin A, Phillips P, Whitelock J, Gill A, Sansom O, Croucher D, Parker B, Pajic M, Morton J, Cox TR#, Timpson P#
Nature Communications (2019)


The extracellular matrix as a key regulator of intracellular signalling networks
Hastings JF*, Skhinas JN*, Fey D, Croucher DR#, Cox TR#
British Journal of Pharmacology (2019)


2018

Recent advances in understanding the complexities of metastasis
Chitty JL*, Filipe EC*, Lucas MC, Herrmann D, Cox TR#, Timpson P#
F1000Research (2018) [Invited Faculty of F1000 review]

Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer
Cazet AS*, Hui MN*, Elsworth BL, Wu SZ, Roden D, Chan CL, Skhinas JN, Collot R, Yang J, Harvey K, Johan MZ, Cooper C, Nair R, Herrmann D, McFarland A, Deng N, Ruiz-Borrego M, Rojo F, Trigo JM, Bezares S, Caballero R, Lim E, Timpson P, O’Toole S, DN Watkins, Cox TR, Samuel MS, Martín M, Swarbrick A
Nature Communications (2018)

Charting the unexplored extracellular matrix in cancer
Filipe EC*, Chitty JL*, Cox TR#
International Journal of Experimental Pathology (2018)

Reshaping the Tumor Stroma for Treatment of Pancreatic Cancer
Vennin C, Murphy KJ, Morton JP, Cox TR, Pajic M, Timpson P
Gastroenterology (2018)

Proteomic Characterisation of Caenorhabditis elegans Larval Development
Xia T*, Horton ER*, Salcini AE, Pocock R, Cox TR#, Erler JT#
Proteomics (2018)


2017

Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer
Chou A, Froio D, Nagrial AN, Parkin A, Murphy KJ, Chin VT, Wohl D, Steinmann A, Stark R, Drury A, Walters SN, Vennin C, Burgess A, Pinese M, Chantrill LA, Cowley MJ, Molloy TJ, Australian Pancreatic Cancer Genome Initiative (APGI), Waddell N, Johns A, Grimmond SM, Chang DK, Biankin AV, Sansom OJ, Morton JP, Grey ST, Cox TR, Turchini J, Samra J, Clarke SJ, Timpson P, Gill AJ, Pajic M
Gut (2017)

Three-dimensional organotypic matrices from alternative collagen sources as pre-clinical models for cell biology
Conway JRW, Vennin C, Cazet AS, Herrmann D, Murphy KJ, Warren SC, Wullkopf L, Boulghourjian A, Zaratzian A, Da Silva AM, Pajic M, Morton JP, Cox TR#, Timpson P#
Scientific Reports (2017)

Dynamic Rearrangement of Cell States Detected by Systematic Screening of Sequential Anticancer Treatments
Koplev S*, Longden J*,  Ferkinghoff-Borg J*, Blicher Bjerregård M, Cox TR, Erler JT, Pedersen JT, Voellmy F, Sommer MOA, Linding R
Cell Reports (2017)

The interplay between extracellular matrix remodelling and kinase signalling in cancer progression and metastasis
Skhinas JN, Cox TR#
Cell Adhesion & Migration (2017)


ISDoT: in situ decellularization of tissues for high-resolution imaging and proteomic analysis of native extracellular matrix
Mayorca-Guiliani AE*, Madsen CD*, Cox TR*, Horton ER, Venning FA, Erler JT
Nature Medicine (2017)
*First authors contributed equally

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis
Vennin C*, Chin VT*, Warren SC, Lucas MC, Herrmann D, Magenau A, Melenec A, Walters SN, del Monte-Nieto G, Conway JRW, Nobis M, Allam AH, McCloy RA, Currey N, Pinese M, Boulghourjian A, Zaratzian A, Adam ASA, Heu C, Nagrial AM, Chou A, Steinmann A, Drury A, Froio D, Giry-Laterriere M, Harris NLE, Phan T, Jain R, Weninger W, McGhee EJ, Whan R, Johns AL, Samra JS, Chantrill L, Gill AJ, Kohonen-Corish M, Harvey RP, Biankin AV, Australian Pancreatic Cancer Genome Initiative (APGI), Evans TRJ, Anderson KI, Gray ST, Ormandy CJ, Gallego-Ortega D, Wang Y, Samuel MS, Sansom OJ, Burgess A, Cox TR, Morton JP, Pajic M, Timpson P
Science Translational Medicine (2017)

Pre-metastatic niches: organ-specific homes for metastases
Peinado H*, Zhang H*, Matei IR*, Costa-Silva B, Hoshino A, Rodrigues G, Psaila B, Kaplan RN, Bromberg JF, Kang Y, Bissel MJ, Cox TR, Giaccia A, Erler JT, Hiratsuka S, Ghajar CM, Lyden D.
Nature Reviews Cancer (2017)

Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer

Chang J*, Lucas M, Leonte L, Garcia-Montolio M, Babloo Singh L, Findlay A, Deodhar M, Foot J, Jarolimek W, Timpson P, Erler JT#, Cox TR# 
Oncotarget (2017)
#Corresponding Author


2016

The Role of Lysyl Oxidase, the Extracellular Matrix and the Pre-Metastatic Niche in Bone Metastasis
Gartland A, Erler JT and Cox TR
Journal of Bone Oncology (2016)

Fibrosis and Cancer: Partners in Crime or Opposing Forces? 
Cox TR# and Erler JT#
Trends In Cancer (2016)
#Corresponding Author

Lysyl Oxidase, a Targetable Secreted Molecule Involved in Cancer Metastasis
Cox TR#, Gartland A, Erler JT
Cancer Research (2016)
#Corresponding Author


2015

Kinome-wide Decoding of Network Attacking Mutations Rewiring Cancer
Creixell P, Schoof EM, Simpson CD, Longden J, Miller CJ, Lou HJ, Perryman L, Cox TR, Zivanovic N, Palmeri A, Wesolowska-Andersen A, Helmer-Citterich M, Ferkinghoff-Borg J, Itamochi H, Bodenmiller B, Erler JT, Turk BE, Linding R
Cell (2015)

Hypoxia and loss of PHD2 inactivate stromal fibroblasts to decrease tumour stiffness and metastasis
Madsen CD, Pedersen JT, Venning FA, Singh LB, Moeendarbary E, Charras G, Cox TR, Sahai E, Erler JT
EMBO Reports (2015)

The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase
Cox TR, Rumney RMH, Schoof EM, Perryman L, Høye AM, Agrawal A, Bird, D, Ab Latif N, Forrest H, Evans HR, Huggins ID, Lang G, Linding R, Gartland A, Erler JT
Nature (2015)


2014

Molecular pathways: connecting fibrosis and solid tumor metastasis
Cox TR# and Erler JT
Clinical Cancer Research (2014)
#Corresponding Author


2013

LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis
Cox TR, Bird D, Baker AM, Barker HE, Ho MW, Lang G, Erler JT
Cancer Research (2013)

Lysyl oxidase plays a critical role in endothelial cell stimulation to drive tumor angiogenesis
Baker AM, Bird D, Welti J, Gourlaouen M, Lang G, Murray G, Reynolds AR, Cox TR, Erler JT
Cancer Research (2013)


2012

The rationale for targeting the LOX family in cancer
Barker HE*, Cox TR* and Erler JT 
Nature Reviews Cancer (2012)
*First authors contributed equally to this work

Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK
Baker AM, Lang G, Bird D, Cox TR#, Erler JT# 
Oncogene (2012)
#Senior authors contributed equally


2011

Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer
Cox TR and Erler JT
Disease Models and Mechanisms (2011)

The Role of Lysyl Oxidase in SRC-Dependent Proliferation and Metastasis of Colorectal Cancer
Baker AM, Cox TR, Bird D, Lang G, Murray GI, Sun XF, Southall SM, Wilson JR, Erler JT
Journal of the National Cancer Institute (2011)


2009

Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche
Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A, Le QT, Giaccia AJ
Cancer Cell (2009)


More Garvan Publications

Staff in the Group

Gretel Major

Research Assistant

Michael Papanicolaou

PhD Student

Shivanjali Ratnaseelan

Honours Student

Yordanos Setargew

Honours Student

Joanna Skhinas

Research Assistant

Michelle Yam

Research Assistant