Area of Research Activity:
- Oncology and cancer biology
- Cell signaling pathways
- Biomarker discovery
- Drug reprofiling
Recent and Past Projects & Publications:
Reprofiling and Repurposing FDA-Approved-Drugs
In this project a genome- and gene-expression-based proprietary approach were used to select specific drug combinations based on their known pharmacological mechanism. The drug reprofiling strategy (also called repurposing, repositioning, or retasking) were then used to reinvestigate drug candidates that have been successfully used in other indication for potential new therapeutic applications in cancer therapy. Several drug combinations have been identified with cytotoxic effects on cancer cells with specific phynotype. These drug combinations are under further investigation and additional testing.
Novel Axin2 (Conductin) Interacting Partners
One of the most reliable approaches for determining the novel function of a given protein is to see if it is interacting with another protein with a known function. Our approach is based on isolating Axin protein assemblies and characterising the components by mass spectrometry (MS). We are also exploring how distruption in these novel Axin-protein complexes lead to human diseases.
Publication:
Sima Salahshor et al (In preparation).
Molecular Study of Axin in Normal and Cancer Cells
Axins (Axin1 and Axin2) are negative regulator of the Wnt signaling pathway as their over-expression results in beta-catenin down-regulation. Axin is able to bring beta-catenin and GSK3s into close proximity, thus facilitating beta-catenin phosphorylation. A variety of in vitro and in vivo studies, suggest that Axin serves as a scaffold protein that binds directly many proteins involved in Wnt signaling pathway. Axin contains several domains that mediate direct binding to APC, GSK3s (GSK3a and GSK3b), beta-catenin, Dishevelled, PP2A, CK1, MEEK1, as well as Axin itself. Deregulation of both Axin1 and Axin2 have been found in different forms of cancer (Sima Salahshor and James R Woodgett). The aim of this project is to explore how Axin deregulation contributes to carcinogenesis.
Reference:
Sima Salahshor and James R Woodgett. The links between Axin and carcinogenesis. Journal of Clinical Pathology (2005); Mar; 58:225-236. [pdf]
Abnormal Wnt Signaling in Pancreas Cancer
In addition to colorectal cancer, we are investigating whether/how defect(s) in Wnt signal transduction contributes to pancreas and esophageal cancer initiation and/or progression. After pancreas cancer, esophageal cancer is the most fatal type of cancer. So far very few genetics abnormalies have been directly linked to this type of disease. Recently, in collaboration with scientists at the Nelson Mandela School of Medicine in South Africa, Ontario Cancer Institute (OCI)/Princess Margaret Hospital (PMH) and the Samuel Lunenfeld Research Institute (SLRI)/ Mount Sinai Hospital (MSH) in Canada, we have shown that many components of the Wnt signal transduction pathway are deregulated in esophageal squamous cell carcinomas. In addition, we have been able to identify a specific type of E-cadherin abnormality that occurs more frequently in esophageal tumors (Sima Salahshor et al, 2008).
References:
Stefano Serra, Sima Salahshor, Mosa Fagih, Firouzeh Niakosari, Jasim M Radhi, Runjan Chetty. Nuclear Expression of E-Cadherin in Solid Pseudopapillary Tumors of the Pancreas. Journal of Pancreas (2007); 8(3):296-303.Runjan Chetty, Stefano Serra, Sima Salahshor, Khaled Alsaad, Warren Shih, Hagen Blaszyk, James R Woodgett, Ming-Sound Tsao. Expression of Wnt-signaling pathway proteins in intraductal papillary mucinous neoplasms of the pancreas: a tissue microarray analysis. Human Pathology (2006); 37:212-217.
Runjan Chetty, Sima Salahshor, B Bapat, Terri Berk, M Croitoru, Steven Gallinger. Intraductal papillary mucinous neoplasm of pancreas in a patient with attenuated familial adenomatous polyposis. Journal of Clinical Patholgy. (2005); 58(1):97-101.
E-cadherin (CDH1) Role in Cancer Initiation and Progression
We have recently identified a specific type of E-cadherin abnormality that occurs more frequently in esophageal tumors (Sima Salahshor et al, 2008). E-cadherin plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Loss of E-cadherin is believed to be an early step in metastatic dissemination. In esophageal cancer, the liver, lungand the bones are the most common sites of metastases. Metastasis is responsible for 90% of the deaths caused by cancer. Learning how E-cadherin funcation will increase our understanding of what triggers cancer cells to start the complicated process of metastasis, and will result in the generation of novel targets for therapies to aid in the prevention of metastasis.
References:
Runjan Chetty, Stefano Serra, Sima Salahshor. E-cadherin in solid pseudopapillary tumors of the pancreas. Human Pathology (2008) Sep;39(9):1407-8.
Runjan Chetty, Stefano Serra, Sima Salahshor. Nuclear Expression of E-cadherin. Am J Surg Pathol (2008) Aug;32(8):1269-70.Stefano Serra, Sima Salahshor, Mosa Fagih, Firouzeh Niakosari, Jasim M Radhi, Runjan Chetty. Nuclear Expression of E-Cadherin in Solid Pseudopapillary Tumors of the Pancreas. Journal of Pancreas (2007); 8(3):296-303.
Sima Salahshor, Richard Naido, Stefano Serra, Warren Shih, Ming-Sound Tsao, Runjan Chetty, James R Woodgett. Frequent accumulation of nuclear E-cadherin and alterations in the Wnt signaling pathway in esophageal squamous cell carcinomas. Modern Pathology (2008) Mar;21(3):271-81. Epub 2007 Dec 14. [pdf]
Sima Salahshor , Huagang Huo , Chieu B. Diep, Anu Loukola, Hong Zhang, Tao Liu, Jindong Chen, Lennart Iselius, Carlos Rubio, Ragnhild A. Lothe, Lauri Aaltonen, Xiao-Feng Su, Gudrun Lindmark, Annika Lindblom. A germline E-cadherin mutation in a family with gastric and colon cancer. International Journal of Molecular Medicine. (2001); 8(4):439-43.
Sima Salahshor , Huagang Huo, Vessela N. Kristensen, Niklas Loman, Sara Sjöberg-Margolin, Anne-Lise Borresen-Dale, Åke Borg, Annika Lindblom. Low frequency of E-cadherin alterations in familial breast cancer. Breast Cancer Research (2001); 3:199-207.
Biomarker Discovery for Early Detection of Colorectal Cancer
Identification of gene products whose abnormal expression can be detected at
early stage of tumor progression could improve the therapeutic index for tumor therapy. Using cDNA microarrays comprising 19,200 human genes (www.microarrays.ca), we have examined the gene expression profile of adenomas and corresponding normal tissues obtained from patients with familial adenomatous polyposis (FAP). Statistical analysis using SAM and GeneTraffic revealed eighty four transcripts to be represented at statistically significant different levels in all adenomas compared to normal tissues (p< 0.05).
Pregnancy specific beta-1 glycoprotein 9 (PSG9) was the most statistically significant candidate in these experiments and therefore was selected for further analysis (Sima Salahshor et al, 2005). This project was originally conducted in collaboration with scientists at Princess Margaret Hospital (PMH) and Mount Sinai Hospital (MSH).
Detailed molecular study of PSG9, as well as other identified tumor markers will help us to develop more accurate method(s) to detect, diagnose, and monitor cancer.
The abnormal expression of the other identified colorectal cancer biomarkers have also been verified in a series of primary tumors. Interestingly, abnormal expression of some of these early markers can also be detected in tumor metastasis.References:
Sima Salahshor, Jason Goncalves, Runjan Chetty, Steven Gallinger, James R Woodgett. Differential gene expression profile reveals deregulation of pregnancy specific b 1 glycoprotein 9 early during colorectal carcinogenesis. BMC Cancer (2005); 5:66.Helene Fischer, Sima Salahshor, Roger Stenling, Jan Björk, Gudrun Lindmark, Lennart Iselius, Carlos Rubio, Annika Lindblom. COL11A1 in FAP polyps and in sporadic colorectal tumors. BMC Cancer (2001); 1(1):17.
Microsatellite Instability (MIN) and Chromosomal Instability (CIN) in Cancer
Chromosomal instability (CIN) includes alterations in chromosome number, chromosome translocation and gene amplification. Microsatellite instability (MSI) refers to mutations in short motifs of tandemly repeated nucleotides resulting from replication errors and deficient mismatch repair (MMR). Most sporadic colorectal cancer show chromosomal instability, while hereditary colorectal cancer (or HNPCC) exhibit microsatellite instability.References:
Sima Salahshor , Konrad Koelble, Carlos Rubio, Annika Lindblom. Microsatellite instability and hMLH1, hMSH2 protein expression in familial and sporadic colorectal cancer. Laboratory Investigation (2001); 81: 535-541.Tao Liu, Jindong Chen, Sima Salahshor, Ewa Holmberg, Henrik Grönberg, Annika Lindblom. Screening families with endometrial and colorectal cancers for germline mutations. Journal of Medical Genetics (2001); 38(9):E29.
Sima Salahshor , Ulf Kressner, Helene Fischer, Gudrun Lindmark, Lars Påhlman, Bengt Glimelius, Annika Lindblom. Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor. British Journal of Cancer (1999); 81(2):190-3.
Sima Salahshor , Ulf Kressner, Lars Påhlman, Bengt Glimelius, Gudrun Lindmark, Annika Lindblom. Colorectal cancer with and without microsatellite instability involves different genes. Genes, Chromosomes and Cancer (1999); 26:247-252.
© 2011 Salahshor