Investigator

James C. Costello

Associate Professor · University of Colorado Denver School of Medicine, Pharmacology

JCCJames C. Costello
Papers(1)
The Capacity of the O…
Collaborators(4)
Jill E. SlanskyMatthew J. SikoraAaron ClausetBenjamin G. Bitler
Institutions(4)
University Of Colorad…Indiana University Sc…University of Colorad…University of Colorad…

Papers

The Capacity of the Ovarian Cancer Tumor Microenvironment to Integrate Inflammation Signaling Conveys a Shorter Disease-free Interval

Abstract Purpose: Ovarian cancer has one of the highest deaths to incidence ratios across all cancers. Initial chemotherapy is effective, but most patients develop chemoresistant disease. Mechanisms driving clinical chemo-response or -resistance are not well-understood. However, achieving optimal surgical cytoreduction improves survival, and cytoreduction is improved by neoadjuvant chemotherapy (NACT). NACT offers a window to profile pre- versus post-NACT tumors, which we used to identify chemotherapy-induced changes to the tumor microenvironment. Experimental Design: We obtained matched pre- and post-NACT archival tumor tissues from patients with high-grade serous ovarian cancer (patient, n = 6). We measured mRNA levels of 770 genes (756 genes/14 housekeeping genes, NanoString Technologies), and performed reverse phase protein array (RPPA) on a subset of matched tumors. We examined cytokine levels in pre-NACT ascites samples (n = 39) by ELISAs. A tissue microarray with 128 annotated ovarian tumors expanded the transcriptional, RPPA, and cytokine data by multispectral IHC. Results: The most upregulated gene post-NACT was IL6 (16.79-fold). RPPA data were concordant with mRNA, consistent with elevated immune infiltration. Elevated IL6 in pre-NACT ascites specimens correlated with a shorter time to recurrence. Integrating NanoString (n = 12), RPPA (n = 4), and cytokine (n = 39) studies identified an activated inflammatory signaling network and induced IL6 and IER3 (immediate early response 3) post-NACT, associated with poor chemo-response and time to recurrence. Conclusions: Multiomics profiling of ovarian tumor samples pre- and post-NACT provides unique insight into chemo-induced changes to the tumor microenvironment. We identified a novel IL6/IER3 signaling axis that may drive chemoresistance and disease recurrence.

121Works
1Papers
4Collaborators

Positions

2013–

Associate Professor

University of Colorado Denver School of Medicine · Pharmacology

Education

2009

Ph.D.

Indiana University Bloomington · Informatics

2004

M.S.

Indiana University Bloomington · Informatics

2002

B.S.

University of Iowa · Biology

2002

B.S.

University of Iowa · Economics

Country

US

Keywords
Prostate CancerSystems BiologyBladder CancerData IntegrationBioinformaticsMathematical ModelingGenomicsMachine Learning