University of Arizona Schroeder Lab

Schroeder Lab MembersRESEARCH

Our lab investigates the changes that occur during cancer progression when tissue structure is lost.  Loss of polarity leads to many aberrant cellular processes, including the mis-regulation of the ERBB oncogene family (including the Epidermal Growth Factor Receptor, HER2 and ERBB3).  Loss of receptor down-regulation upon activation, interaction with novel oncogenic partners and intracellular trafficking that leads to prolonged cellular survival and migration are all promoted by a loss of differentiated polarity programs.  We are focusing on understanding what drives these processes, how they drive oncogenic processes and if we can therapeutically target them.

Our primary focus is on studying metastatic breast cancer, both Triple-Negative/Basal and HER2 positive subtypes. By investigating the interaction between the cells of the tumor, the cells and their microenvironment and the proteins within the cells, we are trying to build a comprehensive picture of essential changes that occur during metastatic cancer progression. We are designing peptide-based therapeutics to then target these processes in an effort to block essential metastasis-driving protein-protein interactions.



Our lab has been funded in the past by the National Cancer Institute, the Department of Defense, Susan G Komen Foundation, the Arizona Biomedical Research Commission, the Ginny Clements Breast Cancer Fund, Susan Greendorfer, and other private donors.

Aberrant Trafficking of the Epidermal Growth Factor Receptor

During cancer progression, EGFR is no longer down-regulated upon activation through its interaction with the apical protein MUC1 (Pochampalli et al 2007 and Pochampalli and Bejjani et al 2007 ). EGFR and MUC1 interactions promote metastatic breast cancer progression through the up-regulation of the metastatic mediator c-Met (Horm et al 2013 ). By using a MUC1 peptide to block the interaction between MUC1 and EGFR, metastatic breast cancer can be strongly inhibited (Bitler et al 2009 and Horm et al 2013).

One of the ways in which MUC1 affects EGFR function is to interfere with the default intracellular trafficking of EGFR. MUC1 and EGFR traffic together in a pattern that leads away from the lysosome to novel intracellular endosomes and the nucleus. Once in the nucleus, EGFR can directly effect the transcription of genes such as CyclinD1 (Bitler et al., 2010 ). We are currently investigating the mechanism by which MUC1 regulates this aberrant trafficking with the goal of discovering a clinically targetable pathway.

EGFR and MUC1 colocalize after EGF treatment

Figure 1. EGFR and MUC1 are found together in breast cancer cells. Under normal conditions EGFR is targeted for degradation while MUC1 remains in vesicles. Here we see EGFR(green) and MUC1(red) together(yellow) distributed throughout the cell, indicating changes promoting cancer.

Polarity as a Tumor Suppressor

Polarity in epithelial cells is regulated by a set of polarity complexes that regulate both apicobasal polarity of the cell and planar polarity of the tissue (both of which are altered during metastatic breast cancer progression, Russ et al., 2012). We are studying how loss of one of these components, Llgl1, affects the ability of the cell to regulate oncogenic processes. We have found that loss of Llgl1 promotes a metastatic survival phenotype, including increased survival, migration and activation of the Cancer Stem Cell mediator TAZ (Greenwood et al., 2016 ). Further, Llgl1 loss promotes the altered trafficking of EGFR, resulting in EGF-dependent activation of TAZ. We are currently investigating the mechanism by which Llgl1 regulates EGF-dependent TAZ activation, focusing on novel membrane targeting and pathway activation.

Model of EGFR and MUC1 interactions in normal tissue, hyperplastic tissue, and tumorous tissue

Figure 2: Breast cancer cells lacking the polarity protein Hugl were stained and the analysis revealed that all mammospheres contained cells of multiple colors indicating the breast tumor precurors did not form from a single cell, but from cells migrating together.

Therapeutic Targeting

Through studying the changes that occur in EGFR regulation during cancer progression, we have learned that novel intracellular trafficking of EGFR is a key component of its oncogenic capacity. The juxtamembrane domain of EGFR is key to its function, in that this 20 amino acid region contains the EGFR dimerization domain (essential for EGFR-dependent signal transduction), its basolateral targeting domain and a nuclear localization domain. Furthermore, it is the region that is responsible for calmodulin binding to EGFR, thereby regulating EGFR-dependent calcium flux in the cell.

We have targeted this portion of EGFR by creating a cell penetrating peptide to enter the cell and bind the EGFR juxtamembrane domain (Hart and Su et al., 2013). This peptide, EJ1, induces inactive ERBB dimers to form, resulting in apoptosis and necrosis of cells in an ERBB-dependent manner. Because EJ1 targets both kinase-dependent and kinase-independent functions of EGFR (and HER2 and ERBB3), it may have stronger efficacy then current ERBB-targeted therapeutics such as Tyrosine Kinase Inhibitors or extracellular antibodies.

We have transferred this discovery to Arizona Cancer Therapeutics, a biotech startup company here at the University of Arizona Cancer Center that is currently performing the IND-enabling studies to bring this promising therapeutic to clinical trials.

Figure 3. Cancer cells treated with EJ1 are killed via apoptosis. In this video, pancreatic cancer cells are treated with EJ1 and red-stained EGF (the stimuli that binds the EGF Receptor). In less than 30 minutes after treatment, large membrane protrusions quickly formed specifically where EGF was concentrated, resulting in focused membrane explosions, highlighting the ability of EJ1 to work in regions specific to the EGF Receptor.

University of Arizona Molecular and Cellular Biology
Arizona Cancer Center
1515 N. Campbell Ave
Tucson, AZ 85724
Laboratory: (520) 626-0207
Fax: (520) 626-3764

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