Cancer trails only cardiovascular disease as the leading cause of mortality in the US. Cancers of the lung, colon, breast and prostate, all derived from epithelium, account for the majority of cancer-related deaths. Recently, our group has made two important discoveries about the various populations of normal and cancer cells in tumors. First, we find that in tumors arising in the breast, colon and head and neck only a subset of the cancer cells, called cancer stem cells, drive the growth and spread of the tumor and are ultimately responsible for patient morbidity and mortality. Next, compared to normal tissue fibroblasts, tumor stroma fibroblasts are """"""""activated"""""""" and make high levels of growth factors implicated in carcinogenesis. The goal of this proposal which is to understand the mechanisms by which colon cancer stem cells interact with the tumor stroma, addresses the central theme of this RFA. As envisioned by the RFA, the investigators are a highly collaborative, multi-disciplinary group drawn from several departments and schools of Stanford University including members from the Departments of Bioengineering, Biochemistry, Statistics, Health Research Policy, Surgery, Medicine and the Stanford Institute of Stem Cell Biology. The team is developing novel, cutting edge technology to understand at the molecular and cellular level how the cancer stem cells interact with the tumor stroma. The grant consists of 2 highly interactive projects as well as an administrative core and a bioinformatics core. Project 1 will obtain gene expression profiles from tumor components including cancer stem cells and normal stromal cells. The gene expression data will be used to identify stromal factors that drive cancer stem cell growth in novel high throughput assays. Project 2 has two parts. We will use microfluidic devices to do single cell gene expression arrays to determine whether there is cellular heterogeneity of the markers described in Project 1 to enrich cancer stem cells. If so, each cell population will be analyzed in Project 1 to determine whether we can further enrich cancer stem cells. The second part will use microfluidic devices to identify stromal cell factors that drive proliferation of colon cancer stem cells. Any factors identified in Project 2 that drive proliferation of the cancer stem cells will be tested in Project 1 to see if the factors cause expansion of cancer stem cells or if they drive them to differentiate into cancer cells that no longer can form a tumor.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA126524-05
Application #
7915640
Study Section
Special Emphasis Panel (ZCA1-SRRB-3 (O1))
Program Officer
Mohla, Suresh
Project Start
2006-09-30
Project End
2011-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
5
Fiscal Year
2010
Total Cost
$927,604
Indirect Cost
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Dalerba, Piero; Sahoo, Debashis; Paik, Soonmyung et al. (2016) CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. N Engl J Med 374:211-22
Isobe, Taichi; Hisamori, Shigeo; Hogan, Daniel J et al. (2014) miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway. Elife 3:
Bockhorn, Jessica; Yee, Kathy; Chang, Ya-Fang et al. (2013) MicroRNA-30c targets cytoskeleton genes involved in breast cancer cell invasion. Breast Cancer Res Treat 137:373-82
Bockhorn, Jessica; Dalton, Rachel; Nwachukwu, Chika et al. (2013) MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11. Nat Commun 4:1393
Dalerba, Piero; Kalisky, Tomer; Sahoo, Debashis et al. (2011) Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nat Biotechnol 29:1120-7
Liu, Huiping; Bockhorn, Jessica; Dalton, Rachel et al. (2011) Removal of lactate dehydrogenase-elevating virus from human-in-mouse breast tumor xenografts by cell-sorting. J Virol Methods 173:266-70
Liu, Huiping; Patel, Manishkumar R; Prescher, Jennifer A et al. (2010) Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc Natl Acad Sci U S A 107:18115-20
Shimono, Yohei; Zabala, Maider; Cho, Robert W et al. (2009) Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138:592-603
Diehn, Maximilian; Cho, Robert W; Clarke, Michael F (2009) Therapeutic implications of the cancer stem cell hypothesis. Semin Radiat Oncol 19:78-86
Diehn, Maximilian; Cho, Robert W; Lobo, Neethan A et al. (2009) Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458:780-3

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