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.
Cell Stem Cell. 2010 Sep 3;7(3):279-82
Ishizawa K, Rasheed ZA, Karisch R, Wang Q, Kowalski J, Susky E, Pereira K, Karamboulas C, Moghal N, Rajeshkumar NV, Hidalgo M, Tsao M, Ailles L, Waddell TK, Maitra A, Neel BG, Matsui W
EMBO Mol Med. 2010 Jul;2(7):275-88
Roos FC, Roberts AM, Hwang II, Moriyama EH, Evans AJ, Sybingco S, Watson IR, Carneiro LA, Gedye C, Girardin SE, Ailles LE, Jewett MA, Milosevic M, Wilson BC, Bell JC, Der SD, Ohh M
Cell Stem Cell. 2009 Dec 4;5(6):579-83
Alexander CM, Puchalski J, Klos KS, Badders N, Ailles L, Kim CF, Dirks P, Smalley MJ
Proc Natl Acad Sci U S A. 2009 Aug 18;106(33):14016-21
Chan KS, Espinosa I, Chao M, Wong D, Ailles L, Diehn M, Gill H, Presti J, Chang HY, van de Rijn M, Shortliffe L, Weissman IL
Neurosurgery. 2009 Aug;65(2):237-49; discussion 249-50; quiz N6
Cheshier SH, Kalani MY, Lim M, Ailles L, Huhn SL, Weissman IL
Methods Mol Biol. 2009;568:175-93
Ailles L, Prince M
Nature. 2009 Apr 9;458(7239):780-3
Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, Joshua B, Kaplan MJ, Wapnir I, Dirbas FM, Somlo G, Garberoglio C, Paz B, Shen J, Lau SK, Quake SR, Brown JM, Weissman IL, Clarke MF
J Clin Oncol. 2008 Jun 10;26(17):2871-5
Prince ME, Ailles LE
Curr Opin Biotechnol. 2007 Oct;18(5):460-6
Ailles LE, Weissman IL
Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):973-8
Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE

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