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:

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

CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment.

We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alone causes apoptotic growth suppression of both PDAC cell lines and organoids, which correlates with loss of MYC expression. CHK1 inhibition also activates ERK and AMPK and increases autophagy, providing a mechanistic basis for increased efficacy of concurrent CHK1 and ERK inhibition and/or autophagy inhibition with chloroquine. To assess how CHK1 inhibition-induced ERK activation promotes PDAC survival, we perform a CRISPR-Cas9 loss-of-function screen targeting direct/indirect ERK substrates and identify RIF1. A key component of non-homologous end joining repair, RIF1 suppression sensitizes PDAC cells to CHK1 inhibition-mediated apoptotic growth suppression. Furthermore, ERK inhibition alone decreases RIF1 expression and phenocopies RIF1 depletion. We conclude that concurrent DDR suppression enhances the efficacy of ERK and/or autophagy inhibitors in KRAS mutant PDAC.
Authors
Klomp, JE; Lee, YS; Goodwin, CM; Papke, B; Klomp, JA; Waters, AM; Stalnecker, CA; DeLiberty, JM; Drizyte-Miller, K; Yang, R; Diehl, JN; Yin, HH; Pierobon, M; Baldelli, E; Ryan, MB; Li, S; Peterson, J; Smith, AR; Neal, JT; McCormick, AK; Kuo, CJ; Counter, CM; Petricoin, EF; Cox, AD; Bryant, KL; Der, CJ
MLA Citation
Klomp, Jennifer E., et al. “CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment.Cell Rep, vol. 37, no. 9, Nov. 2021, p. 110060. Pubmed, doi:10.1016/j.celrep.2021.110060.
URI
https://scholars.duke.edu/individual/pub1502486
PMID
34852220
Source
pubmed
Published In
Cell Reports
Volume
37
Published Date
Start Page
110060
DOI
10.1016/j.celrep.2021.110060

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