Why we focus on Stem Cells in Cancer & Ageing
Stem Cells & Cancer
Due to ever more sophisticated model systems and technologies it has now become clear that cancers are driven by heterogeneity – differences within a cancer cell population – and the plasticity of its subclones; the ability of subsets of the cancer cell population to adapt. We believe cancer stem cells (CSCs) are responsible for this heterogeneity within clonal cell groups - see the image below.
We and other groups have found conclusive evidence to the single-cell level that they represent the root of the disease by giving rise to all differentiated cells within each cancer subclone. Even more importantly, these cells are driving the metastatic behaviour of many cancers and represent an important source for disease relapse. Thus, cancer stem cells should signify a crucial component for any novel treatment approach.
Tumorigenesis and cancer progression
Left: Cancer stem cells can divide without limit, while retaining their stem cell identity (self-renewal) and create progenies with limited proliferative capacity (differentiation). Following genetic or epigenetic changes, both cancer stem cells and non-cancer stem cells become more mobile invasive front of primary tumours.
Centre: Two hypotheses are proposed for the origination of circulating cancer stem cells: (1) some CSCs in the tumour may be more capable of surviving in the blood stream, going on to initiate metastatic spread, or, (2) after a period of dormancy, tumour cells that have already escaped the primary site may somehow convert into circulating cancer stem cells.
Right: Circulating cancer cells must survive the hostile environment of the blood stream, evade immune cell surveillance and leave the blood vessel (extravasate) at a distant location to form metastases. CSCs can also recolonise their tumours of origin, called "tumour reseeding". This selects for highly aggressive CTCs, which are more efficient for metastasis than their parental populations.
Cancer & Ageing
In the UK, 155,000 people aged 70+ years are diagnosed with cancer every year representing 50% of all cancer diagnoses, a number likely to rise as the population ages. Survival rates for older cancer patients lag behind younger patients with the same cancers. We face new problems in understanding the biology of older people who develop cancer, which also includes, but is not limited to, important co-morbidities such as diabetes and metabolic syndrome.
Compelling evidence from BCI indicates that epigenetic controls are fundamental to molecular switches between senescence (cell ageing) and immortalisation. DNA methylation is also a central mechanism underpinning genome stability and gene expression.
Many other hallmarks of ageing have also been implicated as also important determinants of cancer initiation and/or progression:
The Hallmarks of Ageing (modified from Lopez-Otin et al. Cell 2013)
What we do
The BCI pioneers a Centre for Stem Cells in Cancer & Ageing that spans both molecular and patient biology to address the twin issues of cancer and ageing in cancer (stem) cells and in people. Building on our established strength in stem cell biology, we will further expand our laboratory programme to important aspects of our ageing patient population including age-related co-morbidities.
Our interdisciplinary and complementary research programme integrates CSC biology with other BCI groups working on tumour initiation, the microenvironment & inflammation, stem cell biology, drug discovery, and early clinical trials (see below). Our work funded by the ERC advanced investigator grant over the past 5 years has contributed to an improved understanding of CSC biology and function, and set the stage for comprehensive characterisation of CSCs and their microenvironment.
Our interest in using novel technologies to foster diagnosis and treatment of patients with cancer has lead to collaborations with bioengineers at QMUL and beyond (e.g. nanoparticles, microfluidics, bioreactors, lab-on-a-chip), including translational projects with Physician-Scientists at the Barts NHS Trust. Our CSC-centred drug response screening platform ScanCSCTM and its further evolution provides a strong basis for precision medicine approaches with this support.
Embedded research concept.
Interdisciplinary approach for the functional interrogation of cancer stem cells in patients with poor outcome cancers. PDX patient-derived xenografts, GEMM Genetically engineered mouse models, ECMC Experimental Cancer Medicine Centres.
- MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells. Sancho P. et al. Cell Metab. 2015 Oct 6;22(4):590-605. PMID: 26365176
- MiR-93 Controls Adiposity via Inhibition of Sirt7 and Tbx3. Cioffi M et al. Cell Rep. 2015 Sep 8;12(10):1594-605. PMID: 26321631
- Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment. Sainz B Jr et al. Gut. 2015 Dec;64(12):1921-35. PMID: 25841238
- Miranda-Lorenzo I, et al. Intracellular autofluorescence: a biomarker for epithelial cancer stem cells. Nat Methods. 2014 Nov;11(11):1161-9. PMID: 25262208
- Hermann PC, et al. Nicotine promotes initiation and progression of KRAS-induced pancreatic cancer via Gata6-dependent dedifferentiation of acinar cells in mice. Gastro. 2014 Nov;147(5):1119-33.e4. PMID: 25127677