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

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:

Signaling levels mold the RAS mutation tropism of urethane.

RAS genes are commonly mutated in human cancer. Despite many possible mutations, individual cancer types often have a 'tropism' towards a specific subset of RAS mutations. As driver mutations, these patterns ostensibly originate from normal cells. High oncogenic RAS activity causes oncogenic stress and different oncogenic mutations can impart different levels of activity, suggesting a relationship between oncoprotein activity and RAS mutation tropism. Here, we show that changing rare codons to common in the murine Kras gene to increase protein expression shifts tumors induced by the carcinogen urethane from arising from canonical Q61 to biochemically less active G12 Kras driver mutations, despite the carcinogen still being biased towards generating Q61 mutations. Conversely, inactivating the tumor suppressor p53 to blunt oncogenic stress partially reversed this effect, restoring Q61 mutations. One interpretation of these findings is that the RAS mutation tropism of urethane arises from selection in normal cells for specific mutations that impart a narrow window of signaling that promotes proliferation without causing oncogenic stress.
Authors
MLA Citation
Li, Siqi, and Christopher M. Counter. “Signaling levels mold the RAS mutation tropism of urethane.Elife, vol. 10, May 2021. Pubmed, doi:10.7554/eLife.67172.
URI
https://scholars.duke.edu/individual/pub1482861
PMID
33998997
Source
pubmed
Published In
Elife
Volume
10
Published Date
DOI
10.7554/eLife.67172

Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity.

The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate how RAS oncoproteins signal, we mined RAS interactomes for potential vulnerabilities. Here we identify EFR3A, an adapter protein for the phosphatidylinositol kinase PI4KA, to preferentially bind oncogenic KRAS. Disrupting EFR3A or PI4KA reduces phosphatidylinositol-4-phosphate, phosphatidylserine, and KRAS levels at the plasma membrane, as well as oncogenic signaling and tumorigenesis, phenotypes rescued by tethering PI4KA to the plasma membrane. Finally, we show that a selective PI4KA inhibitor augments the antineoplastic activity of the KRASG12C inhibitor sotorasib, suggesting a clinical path to exploit this pathway. In sum, we have discovered a distinct KRAS signaling axis with actionable therapeutic potential for the treatment of KRAS-mutant cancers.
Authors
Adhikari, H; Kattan, WE; Kumar, S; Zhou, P; Hancock, JF; Counter, CM
MLA Citation
Adhikari, Hema, et al. “Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity.Nat Commun, vol. 12, no. 1, Sept. 2021, p. 5248. Pubmed, doi:10.1038/s41467-021-25523-5.
URI
https://scholars.duke.edu/individual/pub1496179
PMID
34504076
Source
pubmed
Published In
Nature Communications
Volume
12
Published Date
Start Page
5248
DOI
10.1038/s41467-021-25523-5

Using BioID to Characterize the RAS Interactome.

Identifying the proteins that associate with RAS oncoproteins has great potential, not only to elucidate how these mutant proteins are regulated and signal but also to identify potential therapeutic targets. Here we describe a detailed protocol to employ proximity labeling by the BioID methodology, which has the advantage of capturing weak or transient interactions, to identify in an unbiased manner those proteins within the immediate vicinity of oncogenic RAS proteins.
Authors
Adhikari, H; Counter, CM
MLA Citation
Adhikari, Hema, and Christopher M. Counter. “Using BioID to Characterize the RAS Interactome.Methods Mol Biol, vol. 2262, 2021, pp. 271–80. Pubmed, doi:10.1007/978-1-0716-1190-6_16.
URI
https://scholars.duke.edu/individual/pub1481789
PMID
33977483
Source
pubmed
Published In
Methods Mol Biol
Volume
2262
Published Date
Start Page
271
End Page
280
DOI
10.1007/978-1-0716-1190-6_16

Expression of transgenes enriched in rare codons is enhanced by the MAPK pathway.

The ability to translate three nucleotide sequences, or codons, into amino acids to form proteins is conserved across all organisms. All but two amino acids have multiple codons, and the frequency that such synonymous codons occur in genomes ranges from rare to common. Transcripts enriched in rare codons are typically associated with poor translation, but in certain settings can be robustly expressed, suggestive of codon-dependent regulation. Given this, we screened a gain-of-function library for human genes that increase the expression of a GFPrare reporter encoded by rare codons. This screen identified multiple components of the mitogen activated protein kinase (MAPK) pathway enhancing GFPrare expression. This effect was reversed with inhibitors of this pathway and confirmed to be both codon-dependent and occur with ectopic transcripts naturally coded with rare codons. Finally, this effect was associated, at least in part, with enhanced translation. We thus identify a potential regulatory module that takes advantage of the redundancy in the genetic code to modulate protein expression.
Authors
Peterson, J; Li, S; Kaltenbrun, E; Erdogan, O; Counter, CM
MLA Citation
Peterson, Jackson, et al. “Expression of transgenes enriched in rare codons is enhanced by the MAPK pathway.Sci Rep, vol. 10, no. 1, Dec. 2020, p. 22166. Pubmed, doi:10.1038/s41598-020-78453-5.
URI
https://scholars.duke.edu/individual/pub1469154
PMID
33335127
Source
pubmed
Published In
Scientific Reports
Volume
10
Published Date
Start Page
22166
DOI
10.1038/s41598-020-78453-5

Exploiting codon usage identifies intensity-specific modifiers of Ras/MAPK signaling in vivo.

Signal transduction pathways are intricately fine-tuned to accomplish diverse biological processes. An example is the conserved Ras/mitogen-activated-protein-kinase (MAPK) pathway, which exhibits context-dependent signaling output dynamics and regulation. Here, by altering codon usage as a novel platform to control signaling output, we screened the Drosophila genome for modifiers specific to either weak or strong Ras-driven eye phenotypes. Our screen enriched for regions of the genome not previously connected with Ras phenotypic modification. We mapped the underlying gene from one modifier to the ribosomal gene RpS21. In multiple contexts, we show that RpS21 preferentially influences weak Ras/MAPK signaling outputs. These data show that codon usage manipulation can identify new, output-specific signaling regulators, and identify RpS21 as an in vivo Ras/MAPK phenotypic regulator.
Authors
Sawyer, JK; Kabiri, Z; Montague, RA; Allen, SR; Stewart, R; Paramore, SV; Cohen, E; Zaribafzadeh, H; Counter, CM; Fox, DT
MLA Citation
Sawyer, Jessica K., et al. “Exploiting codon usage identifies intensity-specific modifiers of Ras/MAPK signaling in vivo.Plos Genet, vol. 16, no. 12, Dec. 2020, p. e1009228. Pubmed, doi:10.1371/journal.pgen.1009228.
URI
https://scholars.duke.edu/individual/pub1468626
PMID
33296356
Source
pubmed
Published In
Plos Genet
Volume
16
Published Date
Start Page
e1009228
DOI
10.1371/journal.pgen.1009228