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Alejandro Sweet-Cordero, MD
Associate Professor of Pediatrics
Stanford University School of Medicine

Phone: (650) 725 5901 ascor@stanford.edu

Lab Contact Information:
265 Campus Drive
LLSCR Building, Rm. G2078b
Stanford, CA, 94305
Phone: (650) 736 2753
Fax : 650 736 0195

Research

  • Kras Signaling
  • Chemotherapy Response
  • Sarcoma Biology

Kras is one of the most frequently mutated genes in human cancer. Many signaling pathways (MAPK, AKT, RALGDS) have been described as being necessary for Kras induced oncogenic transformation. However, the specific pathways required are strongly dependent on the tissue origin (fibroblast vs. epithelial cell etc).

Our laboratory is interested in identifying key regulators of oncogenic Kras function with the ultimate goal of identifying novel "synthetic lethal" interactions that could be used for therapy. Using cross-species microarray analysis to compare a mouse model of lung cancer to human disease, we previously uncovered a gene expression profile associated with Kras mutation across species and in different tissues (Sweet-Cordero, et al Nature Genetics 2005).

We have applied several computational approaches to "reverse engineer" this oncogenic Kras signature and identify key upstream regulators. One of these novel regulators of Kras-driven oncogenesis is Wilm's tumor-1 (WT1). Loss of WT1 leads to senescence in both mouse and human cells that express oncogenic Kras. In addition, we have found that loss of Wt1 significantly decreases lung tumor burden in the Kras G12D/+ mouse model (Vicent et al, Journal of Clinical Investigation, 2010). We are currently carrying out further studies to determine the molecular mechanism underlying the interaction between WT1 and Kras. In addition to Wt1, the lab has also identified several other novel drivers of oncogenic Kras. Lastly, we are particularly interested in how Kras regulates metabolism to promote lung cancer pathogenesis.

Chemotherapy response in vivo

Despite decades of use in clinical medicine, much is still unknown about the molecular and cellular determinants of chemotherapy response in cancer.

Why are some tumors sensitive to chemotherapy treatment whereas others are highly resistant? To what extent are these properties due to genetic mutations in tumor cells (i.e, p53 loss) and to what extent are they determined by the cellular context and microenvironment in which the tumor exists? It is by now well established that important differences exist between how tumor cell in a plastic dish respond to therapy and how tumors in an organism respond to therapy. Therefore, we rely on mouse models that closely recapitulate important aspects of human oncogenesis to study chemotherapy response.

Our group published one of the first studies to comprehensively analyze the response to chemotherapy in a well-characterized mouse model of lung cancer (Oliver et al, Genes and Development, 2010). In this study, we found that p53 loss did not decrease the effect of cisplatin therapy in this model. Furthermore, we found that repeated doses of cisplatin led to the emergence of resistant tumors that showed evidence of increased genomic instability.

Current studies in our laboratory are focused on determining whether cancer stem cells or tumor propagating cells (TPCs) play a role in mediating chemoresistance in murine lung cancer. We have identified a subpopulation of tumor cells in a mouse model of non-small cell lung cancer that have characteristics of TPCs. Preliminary results also suggest that these cells are resistant to chemotherapy (Zheng et al Cancer Cell, 2013).

To study TPCs in vitro, we have developed techniques to do large-scale functional screens in "3D" culture. This work was selected for funding by the highly competitive Innovative Research Grants through Stand Up to Cancer Foundation (www.standup2cancer.org/). In collaboration with the thoracic oncology group at Stanford University Hospital, we have established primary human xenogafts (PDXs), allowing us to extend these studies to human lung cancer.

Biology and genomics of pediatric bone sarcomas. The two most frequent bone sarcomas in children are Osteosarcoma and Ewing's Sarcoma.

Chromosomal translocations are frequent genetic events in the genesis of many human cancers. They are particularly frequent in tumors common in pediatric patients. In Ewing's sarcoma, the most common translocation is EWS/FLI-1. We are using a variety of approaches in both mouse and human primary cells to study the mechanism of EWS/FLI-1 mediated oncogenesis. We have developed a mouse model of Ewing’s sarcoma that closely recapitulates the EWS/FLI-1 translocation. In addition, we have used mesenchymal stem cells isolated from human patients in the pediatric age group to understand the consequences of EWS/FLI-1 translocation in the likely cell of origin. These studies have led us to identify an important role for long, non-coding RNAs in the biology of EWS/FLI-1.

Our laboratory is also interested in Osteosarcoma, another bone cancer that is most commonly seen in adolescents and young adults. In contrast to Ewing's sarcoma, where the initiating genetic event is well understood, the molecular cause of Osteosarcoma is not well defined. A key problem for advancing Osteosarcoma research is that this is a rare disease and primary tumor samples from patients are difficult to obtain. Through a collaboration with several sarcoma centers (UCSF and UW in addition to Stanford), we we have established a large bank of primary xenograft samples from both pre and post-chemotherapy patient biopsies from Osteosarcoma patients. This is a rich resource for translational studies to understand the molecular underpinnings of Osteosarcoma development, chemoresistance and metastasis.