Corinne Linardic

Overview:

Pediatric Sarcomas: Sarcomas are among the most difficult-to-treat cancers in pediatric oncology, with metastatic forms having the highest mortality. We have established genetically defined human cell-based models and genetically engineered murine models for the pediatric skeletal muscle cancer known as rhabdomyosarcoma. Using these models, we can study the causative role of certain genetic changes (e.g. chromosomal translocations and oncogenic RAS) in rhabdomyosarcoma formation and treatment resistance. Specific goals of this research program include the identification of signaling pathways corrupted in rhabdomyosarcoma, with focus on the PAX3-FOXO1 mutation and its downstream effectors and oncogenic RAS, and identification of new therapeutic targets for treatment of this childhood cancer.

Positions:

Associate Professor of Pediatrics

Pediatrics, Hematology-Oncology
School of Medicine

Associate Professor of Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1993

Duke University

M.D. 1995

Duke University

Board Certification Hematology and Oncology

American Board of Pediatrics

Residency, Pediatrics

Children's Hospital of Philadelphia

Fellow, Pediatric Hematology-Oncology, Pediatrics

Children's Hospital of Philadelphia

Fellow, Pediatric Hematology-Oncology, Pediatrics

Duke University

Grants:

A Novel Hippo-Notch axis controlling embryonal rhabdomyosarcoma tumorigenesis

Administered By
Pediatrics, Hematology-Oncology
Awarded By
V Foundation for Cancer Research
Role
Principal Investigator
Start Date
End Date

The role of MST1 in non-canonical Hippo signaling in rhabdomyosarcoma

Administered By
Pediatrics, Hematology-Oncology
Awarded By
Alex's Lemonade Stand
Role
Principal Investigator
Start Date
End Date

Molecular Modeling of Pediatric Skeletal Muscle Tumors

Administered By
Pediatrics, Hematology-Oncology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Investigating co-activator TAZ as a regulator of PAX3-FOXO1, cancer cell stemness, and chemoresistance in fusion-positive rhabdomyosarcoma

Administered By
Pediatrics, Hematology-Oncology
Awarded By
V Foundation for Cancer Research
Role
Mentor
Start Date
End Date

2018 ALSF Million Mile Grant

Administered By
Pediatrics, Hematology-Oncology
Awarded By
Alex's Lemonade Stand
Role
Principal Investigator
Start Date
End Date

Publications:

A method to culture human alveolar rhabdomyosarcoma cell lines as rhabdospheres demonstrates an enrichment in stemness and notch signaling.

The development of three-dimensional cell culture techniques has allowed cancer researchers to study the stemness properties of cancer cells in in vitro culture. However, a method to grow PAX3-FOXO1 fusion-positive rhabdomyosarcoma (FP-RMS) - an aggressive soft tissue sarcoma of childhood - has to date not been reported, hampering efforts to identify the dysregulated signaling pathways that underlie FP-RMS stemness. Here, we first examine the expression of canonical stem cell markers in human RMS tumors and cell lines. We then describe a method to grow FP-RMS cell lines as rhabdospheres and demonstrate that these spheres are enriched in expression of canonical stemness factors as well as Notch signaling components. Specifically, FP-RMS rhabdospheres have increased expression of SOX2, POU5F1 (OCT4), and NANOG, and several receptors and transcriptional regulators in the Notch signaling pathway. FP-RMS rhabdospheres also exhibit functional stemness characteristics including multipotency, increased tumorigenicity in vivo, and chemoresistance. This method provides a novel practical tool to support research into FP-RMS stemness and chemoresistance signaling mechanisms.
Authors
Slemmons, KK; Deel, MD; Lin, Y-T; Oristian, KM; Kuprasertkul, N; Genadry, KC; Chen, P-H; Chi, J-TA; Linardic, CM
MLA Citation
URI
https://scholars.duke.edu/individual/pub1482836
PMID
34004824
Source
pubmed
Published In
Biology Open
Published Date
DOI
10.1242/bio.050211

Expression of oncogenic HRAS in human Rh28 and RMS-YM rhabdomyosarcoma cells leads to oncogene-induced senescence.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. The two predominant histologic variants of RMS, embryonal and alveolar rhabdomyosarcoma (eRMS and aRMS, respectively), carry very different prognoses. While eRMS is associated with an intermediate prognosis, the 5-year survival rate of aRMS is less than 30%. The RMS subtypes are also different at the molecular level-eRMS frequently has multiple genetic alterations, including mutations in RAS and TP53, whereas aRMS often has chromosomal translocations resulting in PAX3-FOXO1 or PAX7-FOXO1 fusions, but otherwise has a "quiet" genome. Interestingly, mutations in RAS are rarely found in aRMS. In this study, we explored the role of oncogenic RAS in aRMS. We found that while ectopic oncogenic HRAS expression was tolerated in the human RAS-driven eRMS cell line RD, it was detrimental to cell growth and proliferation in the human aRMS cell line Rh28. Growth inhibition was mediated by oncogene-induced senescence and associated with increased RB pathway activity and expression of the cyclin-dependent kinase inhibitors p16 and p21. Unexpectedly, the human eRMS cell line RMS-YM, a RAS wild-type eRMS cell line, also exhibited growth inhibition in response to oncogenic HRAS in a manner similar to aRMS Rh28 cells. This work suggests that oncogenic RAS is expressed in a context-dependent manner in RMS and may provide insight into the differential origins and therapeutic opportunities for RMS subtypes.
Authors
Li, JJ; Kovach, AR; DeMonia, M; Slemmons, KK; Oristian, KM; Chen, C; Linardic, CM
MLA Citation
Li, Jenny J., et al. “Expression of oncogenic HRAS in human Rh28 and RMS-YM rhabdomyosarcoma cells leads to oncogene-induced senescence.Sci Rep, vol. 11, no. 1, Aug. 2021, p. 16505. Pubmed, doi:10.1038/s41598-021-95355-2.
URI
https://scholars.duke.edu/individual/pub1494674
PMID
34389744
Source
pubmed
Published In
Scientific Reports
Volume
11
Published Date
Start Page
16505
DOI
10.1038/s41598-021-95355-2

Loss of noncanonical Hippo signaling in fusion-positive alveolar rhabdomyosarcoma increases invasiveness and a dedifferentiated phenotype associated with metastasis.

Authors
Oristian, KM; Crose, LES; Kuprasertkul, N; Bentley, RC; Lin, Y-T; Williams, N; Kirsch, DG; Linardic, CM
MLA Citation
URI
https://scholars.duke.edu/individual/pub1457081
Source
wos-lite
Published In
Molecular Cancer Research : Mcr
Volume
18
Published Date
Start Page
27
End Page
28

Dysregulated Hippo signaling in childhood rhabdomyosarcoma.

Authors
MLA Citation
Linardic, Corinne M. “Dysregulated Hippo signaling in childhood rhabdomyosarcoma.Molecular Cancer Research, vol. 18, no. 8, 2020, pp. 13–14.
URI
https://scholars.duke.edu/individual/pub1457161
Source
wos-lite
Published In
Molecular Cancer Research : Mcr
Volume
18
Published Date
Start Page
13
End Page
14

Genetic and pharmacologic inhibition of HES1 reduces YAP1 expression, impairing rhabdomyosarcoma cell growth.

Authors
Kovach, AR; Linardic, CM
MLA Citation
Kovach, Alexander R., and Corinne M. Linardic. “Genetic and pharmacologic inhibition of HES1 reduces YAP1 expression, impairing rhabdomyosarcoma cell growth.Molecular Cancer Research, vol. 18, no. 8, 2020, pp. 26–26.
URI
https://scholars.duke.edu/individual/pub1457162
Source
wos-lite
Published In
Molecular Cancer Research : Mcr
Volume
18
Published Date
Start Page
26
End Page
26

Research Areas:

Adolescent
Amino Acid Transport Systems
Animals, Genetically Modified
Antibiotics, Antineoplastic
Apoptosis
Base Sequence
Binding Sites
Calcitriol
Carcinogenesis
Cattle
Cell Cycle
Cell Cycle Proteins
Cell Differentiation
Cell Division
Cell Line, Tumor
Cell Proliferation
Cell Survival
Cell Transformation, Neoplastic
Cells, Cultured
Ceramides
Chemokine CXCL12
Cyclin D1
Cyclin-Dependent Kinase Inhibitor p16
DNA-Binding Proteins
Enzyme Activation
Female
Forkhead Transcription Factors
Gene Expression Regulation, Neoplastic
Humans
Intracellular Membranes
Membrane Lipids
Mice
Muscle Neoplasms
Muscle, Skeletal
Mutation
Myoblasts
Myoblasts, Skeletal
Neoplasms
Neoplastic Stem Cells
Nuclear Proteins
Nucleosomes
Oncogene Proteins, Fusion
Oxidative Stress
Paired Box Transcription Factors
Phosphorylation
Promoter Regions, Genetic
Protein Kinase C
Protein Kinase Inhibitors
Protein Kinases
Proto-Oncogene Proteins c-myc
Recombinant Fusion Proteins
Retinoblastoma Protein
Rhabdomyosarcoma
Rhabdomyosarcoma, Embryonal
Signal Transduction
Sirolimus
Sphingolipids
Sphingomyelin Phosphodiesterase
Sphingomyelins
Stereoisomerism
TOR Serine-Threonine Kinases
Telomerase
Tetradecanoylphorbol Acetate
Transcription Factors
Transcription, Genetic
Transcriptome
Transfection
Tumor Cells, Cultured
Tumor Markers, Biological
Tumor Necrosis Factor-alpha
Tumor Suppressor Protein p53
Vascular Endothelial Growth Factor Receptor-1
Xenograft Model Antitumor Assays
ras Proteins