Enzyme Critical to Non-Small Cell Lung Cancer Growth Identified

MedicalResearch.com Interview with:
Teresa W-M. Fan PhD and Andrew N Lane, PhD

Markey Cancer Center, University of Kentucky

Medical Research: What is the background for this study? What are the main findings?

Response:  The study began about eight years ago at the University of Louisville as a collaboration between thoracic surgeon Michael Bousamra II, immunologist Jun Yan and our metabolomics team (T. Fan, R Higashi and A.N. Lane) now at the U. Kentucky. Lung cancer remains as the highest cancer mortality in North America, and is unfortunately often not diagnosed until the most successful treatment, surgery, is no longer an option.  Furthermore although there are numerous subtypes of the disease, the options for chemotherapy are quite limited. We wanted to know how the biochemistry of early stage (resectable) lung cancer differs from that of healthy or at least non-cancerous lung tissue from the point of view of basic tumor biology, and whether we might uncover better option for therapeutic intervention.

To this end, we applied our stable isotope resolved metabolomics (SIRM) technique directly to patients who were diagnosed with resectable NSCLC. By this technique, the fate of individual atoms from a non-radioactive enriched precursor (C-13 glucose in this instance) are traced as they are taken up from the blood and metabolized in situ. This technique, along with model studies with mice, isolated cell cultures, and so-called “Warburg” slices provides tremendous detail about the functional biochemistry of a cancer within its natural microenvironments, compared with non-cancerous tissue. The major finding published in this article is that the anaplerotic enzyme pyruvate carboxylase is greatly upregulated in NSCLC compared with paired non-cancerous lung tissue, whereas the other commonly utilized anaplerotic enzyme glutaminase was not. Interestingly, only cancer cells showed strong staining for pyruvate carboxylase, whereas in the paired non-cancerous lung tissue, only resident macrophages stained for PC. Pyruvate carboxylase was further shown to be essential for tumor growth in both call culture and in mouse xenografts.

Medical Research: What should clinicians and patients take away from your report?

Response:  This study shows that high quality information can be obtained with stable isotope tracing in human subjects, and that this provides unprecedented detail about the workings of tumors- what nutrients are used, how they survive and/or proliferate. While still years away from new treatments, we believe that this approach will hasten discovery of new enzymes as anticancer drug targets, and that the Warburg slice approach may be an important component in the preclinical drug discovery pipeline, ultimately accelerating the bench to beside that is notoriously hampered by the high rate of attrition of oncodrugs in Phase 2 /3 clinical trials.

Medical Research: What recommendations do you have for future research as a result of this study?

Response:  This research is continuing under an NCI-funded program project grant on non-small cell lung cancer, with a focus on the tumor microenvironment and metabolic biochemistry that we call “Systems Biochemistry”. We aim to characterize in greater detail the cellular consequences of pyruvate carboxylase expression, and other metabolic enzymes, as well as modulating the activity of the tumor-infiltrating macrophages, with a view to developing new therapeutics for this deadly cancer.

Citation:

Pyruvate carboxylase is critical for non–small-cell lung cancer proliferation

Published in Volume 125, Issue 2 (February 2, 2015)
J Clin Invest. 2015;125(2):687–698. doi:10.1172/JCI72873.

Katherine Sellers1,2, Matthew P. Fox3, Michael Bousamra, II3,4, Stephen P. Slone5, Richard M. Higashi1,6,7, Donald M. Miller4, Yali Wang4, Jun Yan4, Mariia O. Yuneva2, Rahul Deshpande7, Andrew N. Lane4,6,7 and Teresa W.-M. Fan1,4,6,7

 

MedicalResearch.com Interview with:, & Teresa W-M. Fan PhD and Andrew N Lane, PhD (2015). Enzyme Critical to Non-Small Cell Lung Cancer Growth Identified MedicalResearch.com