Decades of cancer research have led to major breakthroughs in understanding cancer gene function and to important advances in diagnosis and treatment of these complex diseases. Despite this progress, most advanced cancers in adults are ultimately refractory to treatment, and cures for these common conditions remain out of reach. The difficulty in treating advanced cancers relates to many variables, including an incomplete understanding of how cancer initiates, the complexity of the alterations in cancer, heterogeneity in tumors and only a partial understanding of the molecular underpinnings of central cancer pathways. My research program over the next seven years seeks to address important aspects of these fundamental roadblocks. I will address the target cell populations from which cancers emerge - the cell-of-origin - and determine how these early beginnings are linked to one of the most fundamental properties of cancer cells, the acquisition of immortal proliferative properties. I will identify new telomerase-expressing stem cell populations in divers tissues and determine how they relate to cancer cells-of-origin. I will probe the mechanisms by which immortality is acquired by telomerase upregulation and reveal the means by which highly recurrent mutations in the TERT promoter promote tumorigenesis. I will devise methods for disrupting maintenance of the immortal phenotype, ultimately rendering cancer cells incapable of long-term proliferation or survival. Together, this program will lead to fundamental new insights into the origins of cancer, reveal how aspiring cancers circumvent critical bottlenecks they encounter during carcinogenesis and lead to new therapies with potential to treat many of the most refractory human cancers.

Public Health Relevance

Despite important progress in cancer research and treatment, most advanced cancers in adults remain ultimately refractory to treatment, and cures for these common conditions remain out of reach. The difficulty in treating advanced cancers relates to many variables, including a poor understanding of the cancer cell-of-origin, the tissue cell from which the cancer originates. I will investigate the cancer cell-of-origin in diverse cancers, determine how cellular immortality is achieved and discover small molecules that can reverse immortal growth in mature tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA197563-02
Application #
9139884
Study Section
Special Emphasis Panel (ZCA1-GRB-S (M1))
Program Officer
Witkin, Keren L
Project Start
2015-09-08
Project End
2022-08-31
Budget Start
2016-09-01
Budget End
2017-08-31
Support Year
2
Fiscal Year
2016
Total Cost
$972,569
Indirect Cost
$372,569
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Chen, Lu; Roake, Caitlin M; Freund, Adam et al. (2018) An Activity Switch in Human Telomerase Based on RNA Conformation and Shaped by TCAB1. Cell 174:218-230.e13
Lin, Shengda; Nascimento, Elisabete M; Gajera, Chandresh R et al. (2018) Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury. Nature 556:244-248
Garbuzov, Alina; Pech, Matthew F; Hasegawa, Kazuteru et al. (2018) Purification of GFR?1+ and GFR?1- Spermatogonial Stem Cells Reveals a Niche-Dependent Mechanism for Fate Determination. Stem Cell Reports 10:553-567
Roake, Caitlin M; Artandi, Steven E (2017) Approaching TERRA Firma: Genomic Functions of Telomeric Noncoding RNA. Cell 170:8-9
Khincha, Payal P; Bertuch, Alison A; Agarwal, Suneet et al. (2017) Pulmonary arteriovenous malformations: an uncharacterised phenotype of dyskeratosis congenita and related telomere biology disorders. Eur Respir J 49:
Roake, Caitlin M; Artandi, Steven E (2017) Control of Cellular Aging, Tissue Function, and Cancer by p53 Downstream of Telomeres. Cold Spring Harb Perspect Med 7:
Roake, Caitlin M; Artandi, Steven E (2016) DNA repair: Telomere-lengthening mechanism revealed. Nature 539:35-36
Mou, Hongmei; Vinarsky, Vladimir; Tata, Purushothama Rao et al. (2016) Dual SMAD Signaling Inhibition Enables Long-Term Expansion of Diverse Epithelial Basal Cells. Cell Stem Cell 19:217-231
Raval, Aparna; Behbehani, Gregory K; Nguyen, Le Xuan Truong et al. (2015) Reversibility of Defective Hematopoiesis Caused by Telomere Shortening in Telomerase Knockout Mice. PLoS One 10:e0131722
Pech, Matthew F; Garbuzov, Alina; Hasegawa, Kazuteru et al. (2015) High telomerase is a hallmark of undifferentiated spermatogonia and is required for maintenance of male germline stem cells. Genes Dev 29:2420-34