Mutations or expression levels of cell surface receptors are important contributors in cancer signaling. In many settings,  the cellular environment or spatial arrangement of signaling partners is also profoundly altered, resulting in large qualitative changes in signaling outcomes.  The changes are far less understood and often not even part of our standard profiling of cancers.
  
In the context of breast cancer, we study ERBB receptor tyrosine kinases, specifically ERBB2 (HER2) and ERBB3 (HER3) and how changes in the mode of signaling by these receptors explains the efficacy of existing treatments or emergence of drug resistance. We were the first to shown that the relevant signaling unit are transient tetramers instead of dimers, which has direct implications for the mode of action of existing ERBB directed therapeutic antibodies.  The outcome of signaling by these receptors is highly dependent on the placement in raft microdomains within the plasma membrane. Their composition is profoundly altered in cells that experience elevated signaling by ERBB2. The result is a signaling environment that amplifies the oncogenic signaling outcome of ERBB2 signaling. Moreover, ERBB2 gives rise to several truncated species, some of which are far more oncogenic than full size ERBB2 or even other truncated species with minimal differences in sequence or activity.  This difference in oncogenicity reflects differences in the placement within the signaling microenvironments.  The underlying mechanism and adaptation process are under investigation.

In collaboration with the Wilson Laboratory (Chemistry/UM) we have developed a new generation of fluorescent imaging probes that queries the activation state of ERBBs in single live cells.  This provides an entirely novel route to studies of factors that modulate the activity of ERBBs.  It is our goal that next generation probes are suitable for measurements in fixed patient samples, and thereby  improve the stratification of ERBB status in patients for retrospective analysis and ultimately for treatment decisions.

In collaboration with the laboratory of Dr. Vega (Pathology) we also study the mechanism by which Smoothened , a GPCR in the hedgehog signaling pathway, contributes to drug resistance in Diffuse Large B-Cell Lymphoma.  Surprisingly, this activity of SMO does not use one of its established signaling modes. The underlying, novel mechanism involves the assembly of a signal stabilization platform at the membrane and specifically in raft microenvironments. Through the recruitment of multiple partners needed for target deubiquitination / ubiquitination, AKT (and possibly other signaling components) are more effectively recruited, activated and stabilized at the membrane, a setting in which AKT manifests its most potent pro survival signaling.  We are studying the mechanism by which this contributes to resistance to doxorubicin and the resensitization of refractory DLBCL though targeted disruption of this process.