Laurie Ailles, PhD

Characterization of cellular heterogeneity in human solid tumours

The cancer stem cell hypothesis proposes that cancers contain a rare subset of cells, cancer stem cells (CSCs) that can both initiate and propagate the disease. CSCs are functionally distinct from the majority of tumour cells in that they have the capacity for long-term maintenance of tumour growth. CSCs are highly enriched for tumourigenic potential in immune-compromised mice, thus they are better labeled as "tumour-initiating cells" (TICs). The key requirement of the TIC model is the ability to prospectively isolate a population of cells that can generate a serially transplantable tumour with the histological properties and immunophenotype of the initial malignancy. TICs have been identified in a number of solid cancers including brain, breast, colon, pancreas and head & neck. TICs are thought to have unique properties that allow them to evade conventional cytotoxic therapies and furthermore, may be the cause of chemo-radiation resistance.

A key property of TICs is their ability, like normal stem cells, to self-renew. Several embryonically important molecular pathways play key roles post-embryonically in the regulation of somatic stem cell self-renewal, particularly during tissue regeneration and repair, and the maintenance of tissue homeostasis. Many of these pathways have also been implicated in carcinogenesis; there is mounting evidence that the deregulation of these pathways may be key early events that alter the path of somatic stem cells from normal tissue repair to neoplastic proliferation. Alternatively, activation or failed shut-down of a self-renewal pathway may occur in a cell that normally does not self-renew, thereby transforming it into a TIC. Activation status of these self-renewal pathways might thus be distinguishing markers of TICs and, as self-renewal represents a key property necessary for TIC propagation, candidate therapeutic targets.

In addition, data are emerging that TICs possess properties such as quiescence and drug resistance that facilitate survival following standard cancer therapies. However there remains uncertainty as to whether treatment failure is solely a function of TIC properties or if the tumour environment influences whether a cancer cell adopts stem cell properties. Nonetheless, there is a growing appreciation that the presence of stem cell properties within certain cancers alters their response to therapy, and that failure to eliminate TICs will thus increase the risk of relapse. However, experimental work has not yet translated into improved outcomes for patients; it thus remains a major objective to demonstrate that knowledge of TICs will have meaningful relevance beyond model systems and can in fact improve diagnosis and prediction of responses, and guide treatment regimens.

The primary hypothesis for our studies is that the molecular characterization of TICs and their microenvironment in solid tumours will lead to the identification of molecular pathways that mediate TIC self-renewal and/or survival and that this will correlate with clinical outcome. We address this hypothesis through a number of approaches:
  • Identification of markers that allow purification of cell populations from primary patient tumours. These populations are then functionally validated using in vitro and in vivo assays, as well as analyzed at the molecular level to identify candidate pathways and targets.
  • Clinical data is used to determine whether TIC-related properties such as frequency or marker expression can be used as prognostic biomarkers.
  • The cancer-associated fibroblast component of the tumour microenvironment is isolated, propagated, and studied for mechanisms by which they may be supporting TIC function.
Our current work focuses on these questions in head-and-neck squamous cell carcinoma, high grade serous ovarian cancer, and clear cell renal cell carcinoma.
Nat Genet. 2000 Jun;25(2):217-22
Follenzi A, Ailles LE, Bakovic S, Geuna M, Naldini L
Leukemia. 1997 Dec;11(12):2220-1
Hogge DE, Ailles LE, Gerhard B
Blood. 1997 May 1;89(9):3104-12
Blair A, Hogge DE, Ailles LE, Lansdorp PM, Sutherland HJ
Arch Pathol Lab Med. 1992 Sep;116(9):951-4
Young ID, Ailles L, Narindrasorasak S, Tan R, Kisilevsky R
Lab Invest. 1991 May;64(5):709-12
Young ID, Ailles L, Deugau K, Kisilevsky R

Pages


Assistant Professor, Department of Medical Biophysics, University of Toronto
Investigator II, Ontario Institute for Cancer Research