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:

George Barth Geller Distinguished Professor of Pharmacology

Pharmacology & Cancer Biology
School of Medicine

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

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

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:

Signaling amplitude molds the <i>Ras</i> mutation tropism of urethane

Authors
MLA Citation
Li, Siqi, and Christopher M. Counter. “Signaling amplitude molds the Ras mutation tropism of urethane.” Cold Spring Harbor Laboratory. Crossref, doi:10.1101/2021.02.09.430515.
URI
https://scholars.duke.edu/individual/pub1515369
Source
crossref
DOI
10.1101/2021.02.09.430515

Distinct responses to rare codons in select Drosophila tissues.

Codon usage bias has long been appreciated to influence protein production. Yet, relatively few studies have analyzed the impacts of codon usage on tissue-specific mRNA and protein expression. Here, we use codon-modified reporters to perform an organism-wide screen in Drosophila melanogaster for distinct tissue responses to codon usage bias. These reporters reveal a cliff-like decline of protein expression near the limit of rare codon usage in endogenously expressed Drosophila genes. Near the edge of this limit, however, we find the testis and brain are uniquely capable of expressing rare codon-enriched reporters. We define a new metric of tissue-specific codon usage, the tissue-apparent Codon Adaptation Index (taCAI), to reveal a conserved enrichment for rare codon usage in the endogenously expressed genes of both Drosophila and human testis. We further demonstrate a role for rare codons in an evolutionarily young testis-specific gene, RpL10Aa. Optimizing RpL10Aa codons disrupts female fertility. Our work highlights distinct responses to rarely used codons in select tissues, revealing a critical role for codon bias in tissue biology.
Authors
Allen, SR; Stewart, RK; Rogers, M; Ruiz, IJ; Cohen, E; Laederach, A; Counter, CM; Sawyer, JK; Fox, DT
MLA Citation
Allen, Scott R., et al. “Distinct responses to rare codons in select Drosophila tissues.Elife, vol. 11, May 2022. Pubmed, doi:10.7554/eLife.76893.
URI
https://scholars.duke.edu/individual/pub1520273
PMID
35522036
Source
pubmed
Published In
Elife
Volume
11
Published Date
DOI
10.7554/eLife.76893

An ultra-sensitive method to detect mutations in human RAS templates.

The RAS family of small GTPases is mutated in roughly a fifth of human cancers. Hotspot point mutations at codons G12, G13, and Q61 account for 95% of all these mutations, which are well established to render the encoded proteins oncogenic. In humans, this family comprises three genes: HRAS, NRAS, and KRAS. Accumulating evidence argues that oncogenic RAS point mutations may be initiating, as they are often truncal in human tumours and capable of inducing tumorigenesis in mice. As such, there is great interest in detecting oncogenic mutation in the RAS genes to understand the origins of cancer, as well as for early detection purposes. To this end, we previously adapted the microbial ultra-sensitive Maximum Depth Sequencing (MDS) assay for the murine Kras gene, which was capable of detecting oncogenic mutations in the tissues of mice days after carcinogen exposure, essentially capturing the very first step in tumour initiation. Given this, we report here the adaption and details of this assay to detect mutations in a human KRAS sequence at an analytic sensitivity of one mutation in a million independently barcoded templates. This humanized version of MDS can thus be exploited to detect oncogenic mutations in KRAS at an incredible sensitivity and modified for the same purpose for the other RAS genes.
Authors
MLA Citation
Li, Siqi, and Christopher M. Counter. “An ultra-sensitive method to detect mutations in human RAS templates.Small Gtpases, vol. 13, no. 1, Jan. 2022, pp. 287–95. Pubmed, doi:10.1080/21541248.2022.2083895.
URI
https://scholars.duke.edu/individual/pub1523964
PMID
35658790
Source
pubmed
Published In
Small Gtpases
Volume
13
Published Date
Start Page
287
End Page
295
DOI
10.1080/21541248.2022.2083895

Non-canonical genomic driver mutations of urethane carcinogenesis.

The carcinogen urethane induces pulmonary tumors in mice initiated by an incredibly specific Q61L/R oncogenic mutation in the proto-oncogene Kras. Previous Whole-Exome Sequencing of urethane-induced tumors revealed a bias towards A➙T/G and G➙A substitutions. Subsequent ultra-sensitive Maximum-Depth Sequencing of Kras shortly after urethane exposure suggest a further refinement to CA➙CT/G substitutions. As C182AA➙C182T/GA substitutions in Kras result in Q61L/R mutations, the extreme bias of urethane towards these genomic driver mutations can be ascribed to the specificity of the carcinogen for CA➙CT/G substitutions. However, we previously found that changing rare codons to common in the Kras gene to increase protein expression shifted mutations in urethane-induced tumors away from Kras, or when detected in Kras, to G12D mutations that are usually rarely detected in such tumors. Moreover, the loss of p53 partially reversed this effect, generating tumors with either Q61L/R or G12D oncogenic Kras mutations, or no Kras mutations, presumably due to other genomic driver mutations. Determining the origin of these G12D and other unknown non-canonical genomic driver mutations would provide critical insight into the extreme bias of carcinogens for specific genomic driver mutations. We thus compared the types of Single Nucleotide Variations detected by previously performed Maximum-Depth Sequencing immediately after urethane exposure to the mutation signatures derived from Whole Exome Sequencing of urethane-induced tumors. This identified two types of non-canonical mutations. First, a V637E oncogenic mutation in the proto-oncogene Braf that conforms to the mutation signature of urethane, suggesting that the mutational bias of the carcinogen may account for this non-canonical mutation, similar to that for canonical Q61L/R mutations in Kras. Second, G12D and Q61H mutations in Kras that did not fit this mutation signature, and instead shared similarity with Single Nucleotide Variations detected by Maximum-Depth Sequencing from normal cells, suggesting that perhaps these mutations were pre-existing. We thus posit that when canonical Kras mutations are selected against that the carcinogen may instead promote the expansion of pre-existing genomic driver mutations, although admittedly we cannot rule out other mechanisms. Interrogating the mutation signatures of human lung cancers similarly identified KRAS genomic driver mutations that failed to match the mutation signature of the tumor. Thus, we also speculate that the selection for non-canonical genomic driver mutations during urethane carcinogenesis may reflect the process by which discordance between genomic driver mutations and mutational signatures arises in human cancers.
Authors
MLA Citation
Li, Siqi, and Christopher M. Counter. “Non-canonical genomic driver mutations of urethane carcinogenesis.Plos One, vol. 17, no. 4, 2022, p. e0267147. Pubmed, doi:10.1371/journal.pone.0267147.
URI
https://scholars.duke.edu/individual/pub1519414
PMID
35482806
Source
pubmed
Published In
Plos One
Volume
17
Published Date
Start Page
e0267147
DOI
10.1371/journal.pone.0267147

RAS mutation patterns arise from tissue-specific responses to distinct oncogenic signaling

Despite multiple possible oncogenic mutations in the proto-oncogene KRAS , unique subsets of these mutations are detected in different cancer types. As KRAS mutations occur early, if not being initiating, these mutational biases are ostensibly a product of how normal cells respond to the encoded oncoprotein. Oncogenic mutations can impact not only the level of active oncoprotein, but also engagement with effectors and other proteins. To separate these two effects, we generated four novel inducible Kras alleles encoded by the biochemically distinct mutations G12D versus Q61R encoded by native (nat) rare versus common (com) codons to produce either low or high protein levels. Each allele induced a distinct transcriptional response in normal cells. At one end of the spectrum, the Kras natG12D allele induced transcriptional hallmarks suggestive of an expansion of multipotent cells, while at the other end, the Kras comQ61R allele exhibited all the hallmarks of oncogenic stress and inflammation. Further, this dramatic difference in the transcriptomes of normal cells appears to be a product of signaling differences due to increased protein expression as well as the specific mutation. To determine the impact of these distinct responses on RAS mutational patterning in vivo , all four alleles were globally activated, revealing that hematolymphopoietic lesions were sensitive to the level of active oncoprotein, squamous tumors were sensitive to the G12D mutant, while carcinomas were sensitive to both these features. Thus, we identify how specific KRAS mutations uniquely signal to promote the conversion of normal hematopoietic, epithelial, or squamous cells towards a tumorigenic state.
Authors
Erdogan, O; Pershing, NLK; Kaltenbrun, E; Newman, N; Everitt, J; Counter, C
MLA Citation
Erdogan, Ozgun, et al. RAS mutation patterns arise from tissue-specific responses to distinct oncogenic signaling. Dec. 2021. Epmc, doi:10.1101/2021.12.10.472098.
URI
https://scholars.duke.edu/individual/pub1503816
Source
epmc
Published Date
DOI
10.1101/2021.12.10.472098