(514.4) Aberrant glycogen accumulation alters gene expression and promotes lung tumor progression in vivo

Poster Board Number: A383

Jessica Lamb (University of Kentucky), Lindsey Conroy (University of Kentucky), Alexis James (University of Kentucky), Michael Buoncristiani (University of Kentucky), Eric Relich (University of Kentucky), Christine Brainson (University of Kentucky), Ramon Sun (University of Kentucky)

Lung cancer is one of the most prevalent cancers worldwide, accounting for nearly two million new cases each year. Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer and is the leading cause of cancer related mortalities worldwide. LUAD has an extremely poor five-year survival rate, which is likely due to cases being diagnosed at advanced stages and thus being more difficult to treat the metastatic disease. Identifying the molecular processes that contribute to disease progression is a critical goal in lung cancer research that could lead to predictive biomarkers and novel therapies. Glycogen is the primary form of carbohydrate storage in mammalian cells, and its degradation product, Glucose 6-Phosphate (G6P) feeds directly into glycolysis, making glycogen intimately connected to central carbon metabolism. Recently, aberrant glycogen accumulation in lung tumors has been reported to promote lung cancer progression, driven by largely unknown mechanisms. We recently generated a transgenic KRASG12D/p53-/- LUAD mouse model that also lacks the glycogen phosphatase laforin (LKO). This model develops increased glycogen accumulation in the lungs and displays accelerated tumor growth compared to the KRASG12D/p53-/- control (WT), as measured by Ki67 staining. To identify potential biological processes perturbed by LUAD-glycogen, we performed RNA-sequencing on lung tumors resected from WT and LKO mice. We identified over 300 genes that are differentially expressed between WT and LKO lung tumors. Specifically, gene set enrichment analysis (GSEA) revealed genes that were up-regulated in LKO lung tumors were involved in extracellular matrix remodeling, cell-to-cell communication, and cell proliferation. All of these processes are implicated in tumor growth, which supports our initial observation that LKO mice have increased tumor burden and disease progression. Our findings ultimately highlight several potential mechanisms by which LUAD-glycogen promotes LUAD tumor progression, which can be further investigated to identify novel biomarkers and therapeutic targets.

Support or Funding Information

National Institute of Health (NIH) grant: RO1 AG066653, St Baldricks Career Development Award, V-Scholar Grant, Rally Foundation Independent Investigator Grant, and NIH/NCI training grant T32CA165990

lt;pgt;National Institute of Health (NIH) grant: RO1 AG066653,amp;nbsp;lt;span style="font-size: 1em;"gt;St Baldricks Career Development Award,amp;nbsp;lt;/spangt;lt;span style="font-size: 1em;"gt;V-Scholar Grant,amp;nbsp;lt;/spangt;lt;span style="font-size: 1em;"gt;Rally Foundation Independent Investigator Grant, and lt;/spangt;lt;span style="font-size: 1em;"gt;NIH/NCI training grant T32CA165990lt;/spangt;lt;/pgt;