The role of Cripto and cell surface GRP78 in cancer cell plasticity, adaptation to stress and metastasis
We recently published an article showing that this unusual signaling pair (Cripto and GRP78) can promote or maintain the normal stem cell state of isolated mammary stem cells.
Below are 3-dimensional organoids from that study, each comprised of hundreds of cells that arose from a single precursor mammary stem cell. They were grown in the presence of added Cripto protein (middle) or added Cripto inhibitor (right), compared to controls on the left. Cripto blocks the generation of differentiated Cytokeratin 14 expressing cells (stained red and indicated with arrows) and Cytokeratin 8 expressing cells (stained green) while Cripto blockade does the opposite, promoting the production of single positive differentiated cells from the double positive (yellow) cell state. CCripto and Cripto blockade also had opposing effects on molecular signaling, serial passage and mammary gland reconstitution in mice following transplant revealing it as a robust regulator of the mammary stem cell state.
In addition to regulating normal stem cells, Cripto is known to influence diverse cellular processes that are also important for tumor progression (below right). It functions by acting as a cofactor in paracrine signaling of select TGF-β family members and can also act as a paracrine factor itself potentiating both TGF-β family signaling and, through an unknown mechanism, growth factor-like signaling that involves Src/Erk/Akt activation (below right). Though its full mechanism of action remains to be determined, it has been shown that Cripto requires partnering with cell surface exposed GRP78 for its activities. Both proteins are inducible by diverse stresses that are often found in tumors.
We and our collaborators are now using a broad set of molecular profiling approaches, customized in vitro systems, purified recombinant proteins and in vivo cancer models to investigate 1) the molecular mechanisms of Cripto and GRP78 action, 2) the possibility that stresses in tumors are specifically promoting reprogramming to stem cell phenotypes through this pathway and 3) the potential of blocking this signaling as a means of cancer stem cell directed therapy. Below is one such strategy that involves tagging tumor cells with a custom luminescent/fluorescent inducible vector that expresses a unique Cripto specific antagonistic protein.
