The work from our laboratory in the last three decades has provided much impetus for the current recognition and acceptance of the importance of context/microenvironment and extracellular matrix (ECM) in regulation of gene expression, and has underscored the plasticity of both the differentiated state and tumors.
I will discuss why and how we developed, and use, 3-dimensional models of normal mammary gland and mammary tumors from both mice and humans to understand breast cancer, and will present recent work, shedding light on why tissue and organ architecture should become also a parameter in cancer research, and how architecture can regulate tissue-specificity as well as the plasticity of tumors. I will also discuss newer and more complex models we have developed to understand metastasis and dormancy and a screen that has allowed us to discover a new class of ‘oncogenes’ in the EGFR/PI3 Kinase.
We have shown a mechanism to underscore the model of dynamic reciprocity and how the ECM and basement membrane signal to nucleus, via intricate interactions with nuclear actin to provide cell and tissue quiescence, our new discoveries of unique functions for MMPs which may explain why anti-MMP therapies failed, and discovery of a novel movement through kinetic imaging of how a unit of tissue function in the mammary gland (an acinus) is formed in the normal breast, lost in malignancy and reformed by controlling the microenvironment and restoring tissue context and architecture.
We suggest these concepts and models have profound implications for diagnosis, prognosis, drug resistance, dormancy and therapy of cancer.
Some current literature from the Bissell laboratory:
1. Bissell MJ and Hines, WC(2011). Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat Med. 2011. Mar; 17(3): 320-9.
2. Tanner K, Mori H, Mroue R, Bruni-Cardoso A and Bissell MJ (2012) Coherent angular motion in the establishment of multicellular architecture of glandular tissues. Proc Natl Acad Sci U S A. 2012 Jan 25.
3. Lee SY, Meier R, Furuta S, Lenburg ME, Kenny PC, Xu R and Bissell MJ (2012) Identification and characterization of FAM83A, a clinically-relevant cancer-associated gene which interacts with c-RAF and PI3K, and confers EGFR-TKI resistance in breast cancer cells. Journal Clinical Investigation. 2012.
4. Di Modugno F, Iapicca P, Boudreau A, Mottolese M, Terrenato I, Perracchio L, Carstens RP, Santoni A, Bissell MJ*, Nisticò P* [2012]. Splicing program of human MENA produces a previously undescribed isoform associated with invasive, mesenchymal-like breast tumors. Proc Natl Acad Sci U S A. 2012. * The two senior authors contributed equally.
5. Liu H, Radisky DC, Yang D, Xu R, Radisky ES, Bissell MJ*, Bishop JM*. MYC suppresses cancer metastasis by direct transcriptional silencing of α(v) and β(3) integrin subunits. Nat Cell Biol. 2012 May 13;14(6):567-74. *Both senior authors contributed equally. (cover feature.)
6.
Mori H, Lo AT, Ghajar CM, Inman
JL, Alcaraz J, Chen CS, Nelson CM, Zhang H, Mott JD, Bascom JL,
Seiki M, and Bissell MJ(2013). Transmembrane/cytoplasmic, rather than
catalytic, domains of Mmp14 signal to MAPK activation and mammary branching
morphogenesis via binding to integrin β1. Development. Development. 2013
Jan;140(2):343-52. doi: 10.1242/dev.084236.
7. Correia AL, Mori H, Chen EI, Schmitt FC and Bissell MJ (2013). Correia AL, Mori H, Chen EI, Schmitt FC, Bissell MJ. The hemopexin domain of MMP3 is responsible for mammary epithelial invasion and morphogenesis through extracellular interaction with HSP90β. Genes Dev. 2013 Apr 1;27(7):805-17. doi: 0.1101/gad.211383.112.
8. Ghajar CM, Peinado H, Mori H, Matei IR, Evason KJ, Brazier H, Almeida D, Koller A,, Hajjar KA, Stainer D, Chen EI, Lyden D and Bissell MJ (2013). The perivascular niche regulates breast tumor dormancy. Nat Cell Biol. 2013 Jun 2. doi: 10.1038/ncb2767.
9. Boudreau A, Tanner K, Wang D, Geyer FC, Reis-Filho JS, and Bissell MJ (2013). 14-3-3σ stabilizes a complex of soluble actin and intermediate filament to enable breast tumor invasion. Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):E3937-44. doi: 10.1073/pnas.1315022110.
10. Onodera Y, Nam JM and Bissell MJ (2013). Increased sugar uptake and metabolism lead to oncogenic activation via EPAC-Rap1 and O-GlcNAc pathways. J Clin Invest. 2013 Dec 9. doi:pii: 63146. 10.1172/JCI63146.