Christopher Counter

Overview:

The Counter lab studies the molecular mechanisms underlying the evolution of normal cells into cancer. The lab is divided into two major areas studying key features of human cancers.

Immortalization: We have shown that the ability of cancer cells to keep dividing, or become immortal, is a fundamental aspect of tumorigenesis, and is due to elongation of telomeres. Current efforts focus on the molecular biology of telomere-binding proteins in regulating telomere length.

Proliferation: The ability of tumor cells to proliferate inappropriately is a hallmark of cancer. One gene that plays a key role in this process is the oncogene Ras. We have shown that Ras exerts its oncogenic signals through different proteins at different phases of cancer. Current studies focus on how these different pathways promote cancer and how to inhibit their activity.

Positions:

Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Assistant Professor in Radiation Oncology

Radiation Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

B.S. 1990

McMaster University

Ph.D. 1996

McMaster University

Postdoctoral Fellow, Whitehead Institute For Biomedical Research

Massachusetts Institute of Technology

Grants:

Developing inhibitors of RalA function for the treatment of pancreatic cancer

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

The role of dietary copper in melanoma

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Identifying phosphatidylinositol metabolism vulnerabilities in cancer pathways

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Dynamic requirements of Ras signaling during cancer

Administered By
Pharmacology & Cancer Biology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Defining RAS isoform- and mutation-specific roles in oncogenesis

Administered By
Pharmacology & Cancer Biology
Awarded By
University of North Carolina - Chapel Hill
Role
Principal Investigator
Start Date
End Date

Publications:

Capturing the primordial Kras mutation initiating urethane carcinogenesis.

The environmental carcinogen urethane exhibits a profound specificity for pulmonary tumors driven by an oncogenic Q61L/R mutation in the gene Kras. Similarly, the frequency, isoform, position, and substitution of oncogenic RAS mutations are often unique to human cancers. To elucidate the principles underlying this RAS mutation tropism of urethane, we adapted an error-corrected, high-throughput sequencing approach to detect mutations in murine Ras genes at great sensitivity. This analysis not only captured the initiating Kras mutation days after urethane exposure, but revealed that the sequence specificity of urethane mutagenesis, coupled with transcription and isoform locus, to be major influences on the extreme tropism of this carcinogen.
Authors
MLA Citation
Li, Siqi, et al. “Capturing the primordial Kras mutation initiating urethane carcinogenesis.Nat Commun, vol. 11, no. 1, Apr. 2020, p. 1800. Pubmed, doi:10.1038/s41467-020-15660-8.
URI
https://scholars.duke.edu/individual/pub1438048
PMID
32286309
Source
pubmed
Published In
Nature Communications
Volume
11
Published Date
Start Page
1800
DOI
10.1038/s41467-020-15660-8

Utility of telomerase-pot1 fusion protein in vascular tissue engineering.

While advances in regenerative medicine and vascular tissue engineering have been substantial in recent years, important stumbling blocks remain. In particular, the limited life span of differentiated cells that are harvested from elderly human donors is an important limitation in many areas of regenerative medicine. Recently, a mutant of the human telomerase reverse transcriptase enzyme (TERT) was described, which is highly processive and elongates telomeres more rapidly than conventional telomerase. This mutant, called pot1-TERT, is a chimeric fusion between the DNA binding protein pot1 and TERT. Because pot1-TERT is highly processive, it is possible that transient delivery of this transgene to cells that are utilized in regenerative medicine applications may elongate telomeres and extend cellular life span while avoiding risks that are associated with retroviral or lentiviral vectors. In the present study, adenoviral delivery of pot1-TERT resulted in transient reconstitution of telomerase activity in human smooth muscle cells, as demonstrated by telomeric repeat amplification protocol (TRAP). In addition, human engineered vessels that were cultured using pot1-TERT-expressing cells had greater collagen content and somewhat better performance in vivo than control grafts. Hence, transient delivery of pot1-TERT to elderly human cells may be useful for increasing cellular life span and improving the functional characteristics of resultant tissue-engineered constructs.
Authors
Petersen, TH; Hitchcock, T; Muto, A; Calle, EA; Zhao, L; Gong, Z; Gui, L; Dardik, A; Bowles, DE; Counter, CM; Niklason, LE
MLA Citation
Petersen, Thomas H., et al. “Utility of telomerase-pot1 fusion protein in vascular tissue engineering.Cell Transplant, vol. 19, no. 1, 2010, pp. 79–87. Pubmed, doi:10.3727/096368909X478650.
URI
https://scholars.duke.edu/individual/pub761708
PMID
19878625
Source
pubmed
Published In
Cell Transplantation
Volume
19
Published Date
Start Page
79
End Page
87
DOI
10.3727/096368909X478650

Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis.

Ras is mutated to remain in the active oncogenic state in many cancers. As Ras has proven difficult to target therapeutically, we searched for secreted, druggable proteins induced by Ras that are required for tumorigenesis. We found that Ras induces the secretion of cytokine IL6 in different cell types, and that knockdown of IL6, genetic ablation of the IL6 gene, or treatment with a neutralizing IL6 antibody retard Ras-driven tumorigenesis. IL6 appears to act in a paracrine fashion to promote angiogenesis and tumor growth. Inhibiting IL6 may therefore have therapeutic utility for treatment of cancers characterized by oncogenic Ras mutations.
Authors
Ancrile, B; Lim, K-H; Counter, CM
MLA Citation
Ancrile, Brooke, et al. “Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis.Genes Dev, vol. 21, no. 14, July 2007, pp. 1714–19. Pubmed, doi:10.1101/gad.1549407.
URI
https://scholars.duke.edu/individual/pub690959
PMID
17639077
Source
pubmed
Published In
Genes & Development
Volume
21
Published Date
Start Page
1714
End Page
1719
DOI
10.1101/gad.1549407

Genomics and clinical medicine: rationale for creating and effectively evaluating animal models.

Because resolving human complex diseases is difficult, appropriate biomedical models must be developed and validated. In the past, researchers have studied diseases either by characterizing a human clinical disease and choosing the most appropriate animal model, or by characterizing a naturally occurring or induced mutant animal and identifying which human disease it best resembled. Although there has been a great deal of progress through the use of these methods, such models have intrinsic faults that limit their relevance to clinical medicine. The recent advent of techniques in molecular biology, genomics, transgenesis, and cloning furnishes investigators with the ability to study vertebrates (e.g., pigs, cows, chickens, dogs) with greater precision and utilize them as model organisms. Comparative and functional genomics and proteomics provide effective approaches for identifying the genetic and environmental factors responsible for complex diseases and in the development of prevention and treatment strategies and therapeutics. By identifying and studying homologous genes across species, researchers are able to accurately translate and apply experimental data from animal experiments to humans. This review supports the hypothesis that associated enabling technologies can be used to create, de novo, appropriate animal models that recapitulate the human clinical manifestation. Comparative and functional genomic and proteomic techniques can then be used to identify gene and protein functions and the interactions responsible for disease phenotypes, which aids in the development of prevention and treatment strategies.
Authors
Swanson, KS; Mazur, MJ; Vashisht, K; Rund, LA; Beever, JE; Counter, CM; Schook, LB
MLA Citation
Swanson, Kelly S., et al. “Genomics and clinical medicine: rationale for creating and effectively evaluating animal models.Exp Biol Med (Maywood), vol. 229, no. 9, Oct. 2004, pp. 866–75. Pubmed, doi:10.1177/153537020422900902.
URI
https://scholars.duke.edu/individual/pub690947
PMID
15388881
Source
pubmed
Published In
Experimental Biology and Medicine
Volume
229
Published Date
Start Page
866
End Page
875
DOI
10.1177/153537020422900902

Inhibition of telomerase is related to the life span and tumorigenicity of human prostate cancer cells.

PURPOSE: Telomerase, the enzyme that catalyzes the elongation of telomeres, is illegitimately activated in the majority of cancers, including that of the prostate, where it may greatly extend the life span of malignant cells. The inhibition of telomerase by molecular intervention has been shown to lead eventually to cell death in several tumor or in vitro immortalized cell lines and in 1 case prevent tumor growth in vivo. Therefore, we tested whether a similar strategy may be used to limit the tumorigenic potential of late stage prostate cancer cells. MATERIALS AND METHODS: PC-3, LNCaP and DU-145 human prostate cancer cells were infected with a retrovirus encoding a dominant-negative version of the catalytic subunit of telomerase (DN-hTERT). Subclones or polyclonal populations were assayed for DN-hTERT expression, telomerase activity, telomere length, cell life span and in most cases tumorigenicity in nude mice. RESULTS: DN-hTERT expression levels directly correlated with cell life span and tumorigenic growth. PC-3 cells expressing high levels of DN-hTERT died rapidly and failed to form tumors in nude mice, whereas cells expressing the lowest levels proliferated the longest and generated tumors that later spontaneously regressed. Similarly the inhibition of telomerase activity in LNCaP cells was greater than in DU-145 cells and correspondingly LNCaP cells had a shorter life span. CONCLUSIONS: DN-hTERT expression limits the life span and tumorigenic potential of human prostate cancer cells, although the onset of these effects appears to be dictated by the expression level of DN-hTERT. Therefore, telomerase represents an attractive target for potentially managing prostate cancer. Nevertheless, effective means of inhibiting the enzyme may be required for a therapeutically useful outcome.
Authors
Guo, C; Geverd, D; Liao, R; Hamad, N; Counter, CM; Price, DT
MLA Citation
Guo, C., et al. “Inhibition of telomerase is related to the life span and tumorigenicity of human prostate cancer cells.J Urol, vol. 166, no. 2, Aug. 2001, pp. 694–98.
URI
https://scholars.duke.edu/individual/pub690933
PMID
11458119
Source
pubmed
Published In
The Journal of Urology
Volume
166
Published Date
Start Page
694
End Page
698