ECM prompts embedded mammary cells to produce β-casein (red).

STREULI

Biologists long thought that the extracellular matrix (ECM) provided only support and protection for cells. But from the early 1980s on, Mina Bissell of the Lawrence Berkeley Laboratory in California contended that the ECM was a prime influence on cells, transmitting signals that direct gene expression and differentiation (Bissell et al., 1982). A 1991 paper from her lab (Streuli et al., 1991) clinched the case for this view, showing that single mammary cells growing in ECM could fashion a milk protein without stimulation from other cells. Later studies from her group identified the signal-sending component of ECM and revealed how it affected cancer cells.

By 1991, Bissell's lab and others had demonstrated that mammary cells reared on basement membrane, the ECM underlying epithelial layers, form bulbs—just like those that abound in breast tissue and exude milk proteins such as β-casein (Li et al., 1987; Barcellos-Hoff et al., 1989). By contrast, cells nurtured on plastic or collagen did neither, unless they could synthesize and assemble their own basement membrane.

But because cells growing in these cultures were in contact with each other, the possibility remained that cell–cell interactions, not ECM signals, provoked differentiation, Bissell recalls. So instead of growing the mammary cells at high density, her group embedded them in basement membrane gels, leaving many cells with no close neighbors. Most single cells in these gels oozed β-casein, the researchers reported (Streuli et al., 1991), but no single cells embedded in collagen did. By adding antibodies that jammed one of the integrins, the surface receptors that receive messages from the ECM, Bissell slashed β-casein output in the basement membrane gels. But blocking other surface proteins that don't heed the ECM had no effect. “It was the first clear demonstration of the role of an ECM receptor in the regulation of specific gene expression,” says Bissell.

In subsequent studies, Bissell and colleagues followed the signaling pathway from the cell's exterior to the nucleus. They showed, for example, that laminin is the basement membrane protein that prods the cell to activate the β-casein gene (Streuli et al., 1995). At the membrane, two kinds of integrins and the protein dystroglycan work together to recognize laminin (Muschler et al., 1999). The β-casein promoter contains a sequence that responds to ECM directives (Schmidhauser et al., 1992; Myers et al., 1999). Bissell's lab has also probed how ECM signaling influences cancer, showing that tumor cells sport extra integrin receptors and that blocking the receptors with an antibody tames the malignant cells (Weaver et al., 1997).

Barcellos-Hoff, M.H., et al.
1989
.
Development.
105
:
223
–235.

Bissell, M.J., et al.
1982
.
J. Theor. Biol.
99
:
31
–68.

Li, M.L., et al.
1987
.
Proc. Natl. Acad. Sci. USA.
84
:
136
–140.

Muschler, J., et al.
1999
.
Mol. Biol. Cell.
10
:
2817
–2828.

Myers, C.A., et al.
1998
.
Mol. Cell. Biol.
18
:
2184
–2195.

Schmidhauser, C., et al.
1992
.
Mol. Biol. Cell.
3
:
699
–709.

Streuli, C.H., et al.
1991
.
J. Cell Biol.
115
:
1383
–1395.

Streuli, C.H., et al.
1995
.
J. Cell Biol.
129
:
591
–603.

Weaver, V.M., et al.
1997
.
J. Cell Biol.
137
:
231
–245.