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 (Canada)

Ph.D. 1996

McMaster University (Canada)

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

Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability.

In human cancers, oncogenic mutations commonly occur in the RAS genes KRAS, NRAS, or HRAS, but there are no clinical RAS inhibitors. Mutations are more prevalent in KRAS, possibly suggesting a unique oncogenic activity mediated by KRAS-specific interaction partners, which might be targeted. Here, we determine the specific protein interactomes of each RAS isoform by BirA proximity-dependent biotin identification. The combined interactomes are screened by CRISPR-Cas9 loss-of-function assays for proteins required for oncogenic KRAS-dependent, NRAS-dependent, or HRAS-dependent proliferation and censored for druggable proteins. Using this strategy, we identify phosphatidylinositol phosphate kinase PIP5K1A as a KRAS-specific interactor and show that PIP5K1A binds to a unique region in KRAS. Furthermore, PIP5K1A depletion specifically reduces oncogenic KRAS signaling and proliferation, and sensitizes pancreatic cancer cell lines to a MAPK inhibitor. These results suggest PIP5K1A as a potential target in KRAS signaling for the treatment of KRAS-mutant cancers.
Authors
Adhikari, H; Counter, CM
MLA Citation
Adhikari, Hema, and Christopher M. Counter. “Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability.Nat Commun, vol. 9, no. 1, Sept. 2018, p. 3646. Pubmed, doi:10.1038/s41467-018-05692-6.
URI
https://scholars.duke.edu/individual/pub1346498
PMID
30194290
Source
pubmed
Published In
Nature Communications
Volume
9
Published Date
Start Page
3646
DOI
10.1038/s41467-018-05692-6

Defining the cooperative genetic changes that temporally drive alveolar rhabdomyosarcoma.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence. Despite advances in therapy, patients with a histologic variant of RMS known as alveolar (aRMS) have a 5-year survival rate of <30%. aRMS tissues exhibit a number of genetic changes, including loss-of-function of the p53 and Rb tumor suppressor pathways, amplification of MYCN, stabilization of telomeres, and most characteristically, reciprocal translocation of loci involving the PAX and FKHR genes, generating the PAX7-FKHR or PAX3-FKHR fusion proteins. We previously showed that PAX3-FKHR expression in primary human myoblasts, cells that can give rise to RMS, cooperated with loss of p16INK4A to promote extended proliferation. To better understand the genetic events required for aRMS formation, we then stepwise converted these cells to their transformed counterpart. PAX3-FKHR, the catalytic unit of telomerase hTERT, and MycN, in cooperation with down-regulation of p16INK4A/p14ARF expression, were necessary and sufficient to convert normal human myoblasts into tumorigenic cells that gave rise to aRMS tumors. However, the order of expression of these transgenes was critical, as only those cells expressing PAX3-FKHR early could form tumors. We therefore suggest that the translocation of PAX3 to FKHR drives proliferation of myoblasts, and a selection for loss of p16INK4A/p14ARF. These early steps, coupled with MycN amplification and telomere stabilization, then drive the cells to a fully tumorigenic state.
Authors
Naini, S; Etheridge, KT; Adam, SJ; Qualman, SJ; Bentley, RC; Counter, CM; Linardic, CM
MLA Citation
Naini, Sarasija, et al. “Defining the cooperative genetic changes that temporally drive alveolar rhabdomyosarcoma.Cancer Res, vol. 68, no. 23, Dec. 2008, pp. 9583–88. Pubmed, doi:10.1158/0008-5472.CAN-07-6178.
URI
https://scholars.duke.edu/individual/pub719089
PMID
19047133
Source
pubmed
Published In
Cancer Res
Volume
68
Published Date
Start Page
9583
End Page
9588
DOI
10.1158/0008-5472.CAN-07-6178

Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells.

BACKGROUND: The Ral guanine nucleotide-exchange factors (RalGEFs) serve as key effectors for Ras oncogene transformation of immortalized human cells. RalGEFs are activators of the highly related RalA and RalB small GTPases, although only the former has been found to promote Ras-mediated growth transformation of human cells. In the present study, we determined whether RalA and RalB also had divergent roles in promoting the aberrant growth of pancreatic cancers, which are characterized by the highest occurrence of Ras mutations. RESULTS: We now show that inhibition of RalA but not RalB expression universally reduced the transformed and tumorigenic growth in a panel of ten genetically diverse human pancreatic cancer cell lines. Despite the apparent unimportant role of RalB in tumorigenic growth, it was nevertheless critical for invasion in seven of nine pancreatic cancer cell lines and for metastasis as assessed by tail-vein injection of three different tumorigenic cell lines tested. Moreover, both RalA and RalB were more commonly activated in pancreatic tumor tissue than other Ras effector pathways. CONCLUSIONS: RalA function is critical to tumor initiation, whereas RalB function is more important for tumor metastasis in the tested cell lines and thus argues for critical, but distinct, roles of Ral proteins during the dynamic progression of Ras-driven pancreatic cancers.
Authors
Lim, K-H; O'Hayer, K; Adam, SJ; Kendall, SD; Campbell, PM; Der, CJ; Counter, CM
MLA Citation
Lim, Kian-Huat, et al. “Divergent roles for RalA and RalB in malignant growth of human pancreatic carcinoma cells.Curr Biol, vol. 16, no. 24, Dec. 2006, pp. 2385–94. Pubmed, doi:10.1016/j.cub.2006.10.023.
URI
https://scholars.duke.edu/individual/pub690956
PMID
17174914
Source
pubmed
Published In
Current Biology : Cb
Volume
16
Published Date
Start Page
2385
End Page
2394
DOI
10.1016/j.cub.2006.10.023

Rescue of an hTERT mutant defective in telomere elongation by fusion with hPot1.

The protein hPot1 shares homology with telomere-binding proteins in lower eukaryotes and associates with single-stranded telomeric DNA in vitro as well as colocalizing with telomere-binding proteins in vivo. We now show that hPot1 is coimmunoprecipitated with telomeric DNA and that stable expression of this protein in telomerase-positive cells results in telomere elongation, supporting the idea that hPot1 is a bona fide mammalian telomere-binding protein. We previously found that mutations in the N-terminal DAT domain of the hTERT catalytic subunit of telomerase rendered the enzyme catalytically active but unable to elongate telomeres in vivo. This phenotype could be partially rescued by fusion with the double-stranded telomeric protein hTRF2. Given that hPot1 binds to single-stranded DNA in vitro (at the same site that hTERT binds to in vivo), we addressed whether fusion of hPot1 can rescue the DAT mutations more efficiently than that of hTRF2. We now report that a DAT mutant of hTERT is indeed efficiently rescued upon fusion to hPot1. However, this rescue depended on the ability of hPot1 to localize to telomeres rather than binding to DNA per se. These data support a model whereby the DAT domain of hTERT is implicated in telomere-telomerase associations.
Authors
Armbruster, BN; Linardic, CM; Veldman, T; Bansal, NP; Downie, DL; Counter, CM
MLA Citation
Armbruster, Blaine N., et al. “Rescue of an hTERT mutant defective in telomere elongation by fusion with hPot1.Mol Cell Biol, vol. 24, no. 8, Apr. 2004, pp. 3552–61. Pubmed, doi:10.1128/mcb.24.8.3552-3561.2004.
URI
https://scholars.duke.edu/individual/pub700859
PMID
15060173
Source
pubmed
Published In
Molecular and Cellular Biology
Volume
24
Published Date
Start Page
3552
End Page
3561
DOI
10.1128/mcb.24.8.3552-3561.2004