Summary Interactions between cancer cells and their surroundings can trigger essential signaling cues that determine cell fate and influence the evolution of the malignant phenotype. As the primary receptors involved in cell-matrix adhesion, integrins present on the surface of tumor and stromal cells have a profound impact on the ability to survive in specific locations, but in some cases these receptors can also function in the absence of ligand binding to promote stemness and survival in the presence of environmental and therapeutic stresses. Understanding how integrin expression and function is regulated in this context will enable the development of new therapeutic approaches to sensitize tumors to therapy and suppress their metastatic phenotype.

Tumor cells, with stem-like properties, are highly aggressive and often display drug resistance. Here, we reveal that integrin αvβ3 serves as a marker of breast, lung, and pancreatic carcinomas with stem-like properties that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitro and in mice bearing patient-derived tumor xenografts or in clinical specimens from lung cancer patients that had progressed on erlotinib. Mechanistically, αvβ3, in the unligated state, recruits KRAS and RalB to the tumor cell plasma membrane, leading to the activation of TBK-1/NFκB. In fact, αvβ3 expression and the resulting KRAS/RalB/NFκB pathway were both necessary and sufficient for tumor initiation, anchorage-independence, self-renewal, and erlotinib resistance. Pharmacological targeting of this pathway with Bortezomib reversed both tumor stemness and erlotinib resistance. These findings not only identify αvβ3 as a marker/driver of carcinoma stemness but they reveal a therapeutic strategy to sensitize such tumors to RTK inhibition.

SUMMARY While molecular subtypes of glioblastoma (GBM) are defined using gene expression and mutation profiles, we identify a unique subpopulation based on addiction to the high affinity glucose transporter, Glut3. Although Glut3 is a known driver of a cancer stem cell phenotype, direct targeting is complicated by its expression in neurons. Using established GBM lines and patient-derived stem cells, we identify a subset of tumors within the “Proneural” and “Classical” subtypes that are addicted to aberrant signaling from integrin αvβ3 that activates a PAK4-YAP/TAZ signaling axis to enhance Glut3 expression. This defined subpopulation of GBM is highly sensitive to agents that disrupt this pathway, including the integrin antagonist cilengitide, providing a targeted therapeutic strategy for this unique subset of GBM tumors.

The facilitatory influence of a "high" dose of PD128,907 upon locomotion is mediated by postsynaptic D(2) receptors and, possibly, countered by their D(3) counterparts. Correspondingly, selective blockade of D(2) but not of D(3) receptors alone suppresses motor function. The reduction in locomotion provoked by a "low" dose of PD128,907 may be mediated by D(2) autoreceptors, but a role of postsynaptic D(3) receptors cannot be excluded. Finally, mechanisms underlying the contrasting influence of chemically diverse D(3) receptor antagonists upon locomotion remain to be elucidated.