H. Rosie Xing, Ph.D.

Regulation of ErbBs and Oncogenic Ras Signaling in Human Oncogenesis, Metastatic dissemination and Tumor Response to Therapeutic Interventions

Research Summary

The core of research conducted at Xing’s Lab is a basic science-driven, mechanistic-based translational cancer biology program. Our main goals are to define molecular mechanisms that govern gain of function (gf) Ras signaling of human oncogenesis and metastatic dissemination via activated epidermal growth factor receptors (EGFRs)/ErbBs, or oncogenic activation of Ras, and to translate this information to develop mechanism-based therapeutic strategies for cancer prevention or treatment.

            The research in the Xing laboratory is currently focused on the following areas of investigation:

1. Regulation of EGFR/ErbB signaling network in oncogenesis and tumor response to anti-EGFR therapies in human head and neck cancer: Squamous cell carcinoma (SCC) of the head and neck (HNSCC) is the sixth most common malignant disease worldwide. While over 80% of the human head and neck squamous cell carcinoma (HNSCC) overexpress EGFR, the particular mechanisms by which signals mediated via EGFR on the cell surface lead to the enhanced malignant phenotypes of HNSCC cancer cells are only partially elucidated and the overall clinical response to anti-EGFR therapies remain low. Thus, a more thorough understanding of the role of EGFR in the molecular pathogenesis of HNSCC is fundamental to the effective utilization of anti-EGFR therapies to treat HNSCC.

            The net effect of EGFR-mediated biologic responses is dependent on the presence and expression level of ErbB co-receptors (ErbB2, 3 and 4), the availability of soluble and/or tethered autocrine and paracrine ligands, and their affinity for the ErbB receptors expressed to be integrated into the activation of downstream signaling matrices. We are currently working on projects to: (i) investigate the molecular mechanisms regulating signaling events and interactions between the EGFR, other EGFR family members (ErbB2, 3, and 4) and their specific ligands in HNSCC and the biological consequences of these interactions in regulating tumor response to anti-EGFR therapies, and (ii) to identify alternative signaling mechanisms that could substitute EGFR/ErbB signaling and give arise to resistance to anti-EGFR therapies.

2. Kinase suppressor of Ras (KSR1) as a novel regulator for ErbB receptors signaling in human breast cancer oncogenesis and progression: KSR1 is identified as an immediate downstream effector selective for gain-of-function (gf) Ras/EGFR. Genetic studies from Ksr1-deficient C. elegans and mice demonstrate that while ksr1 is dispensable for normal development, it may be obligate for gf Ras/EGFR signaling through the MAPK cascade. Ksr1 deficient mice exhibited a hair follicle development defect that is also manifested by the egfr1 knockouts indicating that mammalian KSR1 is required for EGFR1 signaling (REF). In addition, tumor formation in Tg.AC mice resulting from skin-specific oncogenic v-Ha-ras expression was abrogated in Ksr1 knockouts (REF). KSR1 inactivation via genetic and pharmacologic antisense approaches (KSR1 AS-ODN) abrogated gf Ras-mediated tumorigenesis induced by constitutively activated EGFR1 or oncogenic K-Ras mutation in several human tumor cell lines and in nude mice xenografts (REF). These results have identified KSR1 as a novel drug target for gf Ras/EGFR-dependent human malignancies. We are currently developing anti-KSR agents for pre-clinical and clinical testing.     

While Ras gene mutations are rare in cancers of the breast, hyperactivation of the wild-type Ras via elevated expression and/or amplification of members of the EGFR family, especially EGFR/ErbB1 and ErbB2, frequently occur in this cancer. The EGFR family members share many structural and functional characteristics, yet each member has a unique function. However, little is known about upstream regulatory elements that discriminate the multiple downstream effector pathways utilized by each EGFR isoform.

            To explore the role of KSR1 in breast cancer oncogenesis and progression, we generated a panel of human breast cancer cell lines that responded to growth inhibition by pharmacologic inactivation of KSR1 to stably express wild-type KSR1 (KSR-S), antisense KSR1 (KSR-AS) or a dominant-negative kinase inactive KSR1 (DN-KSR). In addition, we successfully established and characterized the physiological relevant mammary epithelial 3-D acini culture in Matrigel that has been shown to optimally distinguish the phenotypic differences between the normal and malignant mammary epithelial cells. This model is currently utilized to investigate the role of KSR1 in regulation of EGFR/ErbB2 signaling of mammary malignant transformation and invasion. The impact of KSR1 activation status on breast cancer tumorigenesis and progression in vivo will be evaluated using orthotopic models of human and mouse breast cancer. The feasibility of treating early-stage and metastatic human breast cancer upon KSR1 AS-ODN treatment will be explored both in vitro and in vivo.

3. KSR1 as a key mediator of EGFR and oncogenic Ras regulation of tumor response to ionizing radiation:  Although ionizing radiation (IR) remains a primary treatment for human cancers, the failure to respond to radiation therapy limits the efficacy of this regimen. While signal transduction events, especially those mediated by the oncogenic Ras and hyper activated EGFR, have been implicated to confer radiation resistance, the underlying mechanism is poorly understood. Ionizing radiation-induced activation of cytoprotective and mitogenic intracellular signaling pathways is dependent on the EGFR. We obtained preliminary results demonstrating KSR1 as a key mediator of EGFR signaling in response to ionizing radiation and as a novel target for radio sensitization. We are currently investigating molecular mechanisms (DNA damage repair, repopulation, cell cycle control etc) governing cellular sensitivity to IR and to regulate radio sensitivity by manipulating EGFR/Ras signal transduction events via KSR1 in vitro and in vivo.

4. Whole-body optical imaging in animal models to access cancer development, progression, metastatic dissemination and tumor response to therapeutic treatments. Molecular imaging permits noninvasive detection of cellular and molecular events by using highly specific probes and gene reporters in living animals, and by adding spatial and temporal dimensions to biological processes in vivo. Whole-body optical imaging, either bioluminescent or fluorescent, is a very versatile, sensitive, and powerful tool for molecular imaging in small animals.  It has allowed semi-quantitative measurements and tracking the fate of tumor cells during tumor progression, metastasis, and treatment response. We are currently investigating the feasibility of employing optical in vivo imaging technologies (2-D planner imager and 3-D tomographic imager) and novel near infrared molecular probes to monitor, characterize, visualize and quantify tumor vascular changes, micrometastasis and tumor-host interactions in real-time using fluorescent labeled orthotopic human or mouse tumor models. We will also monitor the response of the primary tumor and the metastatic lesions to therapeutic interventions, especially the vascular changes to targeted therapies.

Selected Papers