The goal of our research is to understand how the microenvironment drives transcription to generate heterogeneity with tumours, a major cause of therapeutic resistance, and ultimately to develop more effective anti-cancer agents that take heterogeneity into account. Using melanoma as a model, we have identified the molecular mechanisms enabling cells to undertake dynamic and reversible phenotype switches.
Since we first uncovered a melanocyte-specific cell cycle regulator termed the Microphthalmia-associated transcription factor (MITF), we have been examining the role and regulation of a transcription factor cascade that controls melanoma differentiation, proliferation and senescence. We have produced a model in which tumour heterogeneity is driven by reversible microenvironment-mediated cell fate switches, between three populations of cells circumscribed by their differentiated, proliferative or invasive/stem cell-like phenotypes. We show that cell identity is controlled by the levels and post-translational modifications of the Mitf transcription factor. In turn, MITF is regulated by Brn-2; and senescence is bypassed by the activity of the Tbx2 and Tbx3 factors. These factors work together to integrate the output from key signalling pathways with the nutritional status of cells to make cell fate decisions that parallel those made in development.
We also have identified a novel class of regulatory proteins, termed promoter education factors, that are required for the function of classical transcription activators and provide a transcription memory function by mediating the post-transcriptional interaction of a specific gene with nuclear pore components.
Future work will aim to balance and combine our interest in the basic mechanisms of gene regulation with our desire to translate our results on melanoma to the clinic. We aim to use a combination of cell and molecular biology, integrative genomics and high-throughput screening to:
1. Understand how signalling pathways are interpreted by transcription factors to drive phenotype switching and suppress senescence in melanoma.
2. Decipher the molecular events underlying transcriptional memory in melanoma.
3. Deliver to the clinic a novel and effective anti-melanoma therapy based on the capacity of small molecules to direct cells to a therapeutically-sensitive phenotype.
Saez-Ayala, M., Montenegro, M.F., Sanchez-del-Campo, L., Fernandez-Perez, M.P., Chazarra, S., Freter, R., Middleton, M., Pinero-Madrona, A., Cabezas-Herrera, J., Goding, C.R. and Rodriguez-Lopez, J.N. Directed phenotype-switching as a novel anti-melanoma strategy, Cancer Cell in press.
Delmas, V., Beermann, F., Martinozzi, S., Carreira, S., Ackermann, A.,
Kumasaka, M., Denat, L., Goodall, J., Demirkan, N., Goding, C.R., and
Larue L. (2007) b-catenin suppresses p16INK4a expression to bypass senescence
and predispose to melanoma. Genes & Dev 21, 2923-2935.
Carreira, S., Goodall, J. Denat, L., Rodriguez, M., Nuciforo, P, Hoek,
K.S., Testori, A., Larue, L. and Goding, C.R. (2006) Mitf regulation
of Dia1 controls melanoma proliferation and invasiveness. Genes & Dev
Carreira, S., Goodall, J., Aksan, I., La Rocca, S.A., Galibert, M.-D.,
Denat, L., Larue, L. and Goding, C.R. (2005) Mitf cooperates with Rb1
and activates p21Cip1expression to regulate cell cycle progression. Nature
Martinez-Campa, C, Politis, P., Moreau, J.-L., Kent, N., Goodall, J.,
Mellor, J. and Goding C.R. (2004) Precise nucleosome positioning and
the TATA box dictate requirements for the histone H4 tail and the bromo-domain
factor Bdf1. Molecular Cell 15, 69-81.
Vance, K.W., Carreira, S. Brosch, G. and Goding C.R. (2005) Tbx2 is
overexpressed and plays an important role in maintaining proliferation
and suppression of senescence in melanomas. Cancer Res. 65, 2260-2268.
Moreau, J-L., Lee, M., Mahachi, M., Vary, J., Mellor, J., Tsukiyama,
T., and Goding, C.R. (2003) Regulated displacement of TBP from the PHO8
promoter in vivo requires Cbf1 and the Isw1 chromatin remodeling complex.
Molecular Cell 11,1609-1620.