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Research interests

Stromal rigidity as a driver of pancreatic cancer cell proliferation

In ductal adenocarcinoma of the pancreas (PDA), an extensive stromal reaction drives tumour progression and contributes to the lethality of the disease. An understanding of the causes of this desmoplastic response, and the consequent effects of an altered extracellular niche on tumour cell growth, invasion and resistance, would therefore be a pivotal step in the quest to improve patient outcomes.

The inflammatory and fibrotic responses in PDA are the result of complex interplay between tumour and host cells. A universal feature is the generation of a dense and highly rigid stromal extracellular matrix (ECM) that, based on analyses of the adhesion-dependent control of cell phenotype in other systems, is likely to alter proliferation, migration and differentiation. Despite the importance of stromal rigidity to fate determination, a lack of methodologies to manipulate and investigate force sensing in vivo has retarded progress. These methods are now available, so it is timely to determine how stromal rigidity drives tumour progression. The focus of this programme will be the effects of rigidity on proliferation, but our findings will also provide insights into other processes, including metastasis and survival.

Three central hypotheses are being tested:

  1. That the sensing of stromal rigidity originates at the adhesion nexus, the junctional structure that links cells to the ECM via integrin receptors. We propose that alterations in the chemical, mechanical and topological features of the ECM are relayed by integrins and transduced into intracellular signals that control cell fate. There is burgeoning evidence that this is the case, but the mechanisms are only partially elucidated.
  2. That high stromal rigidity impedes the changes in cell architecture needed for accurate segregation of chromosomes and daughter cell separation during mitosis. We propose that cells have evolved mechanisms to monitor adhesive status, and that mechanical cues in the extracellular environment are converted into signals linking to one or more cell cycle checkpoints. Thus, integrated extracellular rigidity may sit alongside DNA damage, cell size and metabolic status as a factor that feeds into decisions whether to replicate DNA, commit to mitosis or partition chromosomes.
  3. That driver mutations in cancers lead to a rewiring of signalling networks, one outcome of which is evasion of these checkpoint control mechanisms. We propose that the desmoplastic response in carcinoma forces proliferation under unfavourable circumstances and accelerates tumour progression over an extended timeframe by increasing proliferation rate and/or genome instability. Interventions that overcome tumour-specific alterations in force sensing could therefore be used alongside conventional therapies to achieve improved outcomes.

In this programme, we are building on our extensive knowledge base of integrin-mediated adhesion and the specialist methodologies that we have pioneered over the past decade to elucidate integrin function, and applying both to models of PDA. We are establishing new techniques for global analyses of the adhesion nexus in three-dimensional (3D) pancreatic organoids and defining how variations in extracellular rigidity initiate signalling at this site to influence cell cycle progression. We hope then to perturb the function of candidate molecules in organoids using knockdown and pharmacological inhibition, and employ molecular cell biology approaches to pinpoint how the sensory mechanisms vary between wild type (WT) and tumour cells. Our immediate objectives for the next five years will be:

  1. Definition of tumour-specific alterations in force-sensitive components of the adhesion nexus.
  2. Determination of the mechanisms whereby rigidity influences cell proliferation.

We hope therefore to answer fundamental questions about the proteins that control normal cell behaviour, how these proteins are altered in disease, and how these changes convert normal cells into cancer cells. The outcomes of the programme will advance our understanding of cancer in two ways: by defining how the adhesive stromal microenvironment influences tumour cell proliferation, and by identifying potential clinical targets in a cancer of massive unmet need. These findings will be relevant not only to PDA but to other highly desmoplastic cancers, such as breast, prostate and colon.

Overview

In pancreatic ductal adenocarcinoma, an extensive stromal reaction drives tumour progression and contributes to the lethality of the disease. An understanding of the causes of this desmoplastic response, and the consequent effects of a highly rigid stromal extracellular matrix on tumour cell phenotype, would therefore be a pivotal step in the quest to improve patient outcomes. Methods are now available to investigate force sensing in vivo, so it is timely to determine how stromal rigidity drives tumour proliferation. 

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being
  • SDG 5 - Gender Equality
  • SDG 7 - Affordable and Clean Energy

External positions

Vice-President (non-clinical), Academy of Medical Sciences

20122017

Research Beacons, Institutes and Platforms

  • Cancer
  • Digital Futures

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