Colorectal cancer (CRC) is the leading cause of cancer-related death in the United States. Cancer death in CRC is mainly due to tumor recurrence and distant metastasis. Sprouty2 (SPRY2), an endogenous suppressor of receptor tyrosine kinase (RTK)/ Mitogen Activated Protein Kinase (MAPK) signaling pathways, acts as a tumor suppressor in breast, prostate, and liver cancer. We discovered oncogenic role of SPRY2 in CRC. The objectives of this application are to assess the requirement and significance of SPRY2 in CRC progression, treatment and recurrence. Studies demonstrated that upregulation of SPRY2 accentuates cancer phenotype whereas suppression of SPRY2 augments epithelial features and decreases epithelial mesenchymal transition (EMT). We hypothesize that deletion of SPRY2 will suppress CRC. To test this hypothesis, in AIM 1, SPRY2 LoxP/Vil-Cre ERT2 mouse model will be utilized. Effect of SPRY2 deletion on azoxymethane (AOM)-induced colonic tumorigenesis will be studied. It was further established that SPRY2 stable transfection significantly increased RTK cMet expression. Suppression of SPRY2 decreased endogenous and TGF-? induced cMet protein and mRNA expression.
In AIM 2, we will delineate TGF-?/SPRY2 dependent transcriptional regulation of cMET in colon cancer cell lines. While inhibitors of epidermal growth factor receptor (EGFR) are beneficial in the treatment of metastatic CRC, increases in cMet expression and EMT are resistance mechanism to anti-EGFR therapy.
In AIM 3, effect of SPRY2 suppression on tumor growth (xenograft model) and metastasis (cecal implantation model) of gefitinib and cetuximab- resistant colon cancer cell lines will be investigated. We hypothesize that SPRY2 suppression will sensitize gefitinib and cetuximab-resistant colon cancer cells to anti-EGFR therapy. Studies will be extended to analyze effect of SPRY2 deletion during gefitinib treatment in vivo SPRY2 LoxP/Vil-Cre ERT2 mouse model. Significance of SPRY2 with tumor recurrence and long-term survival is not clear.
In AIM 4, we hypothesize that SPRY2 expression in primary tumors may correlate directly with tumor recurrence and long-term survival. Further, as SPRY2 is the key regulator of Ras-dependent pathways, we have extended our investigations to assess the association of SPRY2 expression with Ras mutations [KRAS (codon 12, 13) and NRAS (codon 12, 13)] in recurrence. Implication of concomitance of SPRY2 expression and Ras mutations in primary tumors to disease outcome will be investigated. For this analysis sporadic stage II-III archived formalin-fixed paraffin embedded tumors (FFPET) that are linked to outcomes at 5 years will be utilized. To our knowledge, this is the first study to demonstrate a cancer promoting role of SPRY2 in CRC. We have established hypotheses based on our preliminary data and publications. The proposed study is a multi-pronged approach to assess the effect of SPRY2 deletion on tumor growth, examine the role of SPRY2 in acquired resistance to anti-EGFR therapy and evaluate the significance of SPRY2 and Ras mutations in identifying patients with increased risk of tumor recurrence.

Public Health Relevance

Efforts to identify effective strategies to prevent and treat colorectal cancer (CRC) have received increasing attention. In this regard, Sprouty2 is considered a gene that suppresses tumor progression in experimental models of other malignancies. On the contrary, we discovered that Sprouty2 augments growth and metastatic abilities of colon cancer cells. This grant application will assess the role of Sprouty2 in tumor growth, metastasis, treatment, and recurrence. We strongly believe that suppression of this gene will help CRC patients.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Oncology C (ONCC)
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Harry S. Truman Memorial VA Hospital
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Zhang, Qiong; Shim, Katherine; Wright, Kevin et al. (2016) Atypical role of sprouty in p21 dependent inhibition of cell proliferation in colorectal cancer. Mol Carcinog 55:1355-68
Zhang, Q; Wei, T; Shim, K et al. (2016) Atypical role of sprouty in colorectal cancer: sprouty repression inhibits epithelial-mesenchymal transition. Oncogene 35:3151-62
Vaish, Vivek; Khare, Tripti; Verma, Mukesh et al. (2015) Epigenetic therapy for colorectal cancer. Methods Mol Biol 1238:771-82
Khare, Sharad; Verma, Mukesh (2012) Epigenetics of colon cancer. Methods Mol Biol 863:177-85