Thoracic
Akhil Goud Pachimatla
Post-Doctoral Research Affiliate
Roswell park Comprehensive Cancer center
Buffalo, New York, United States
Akhil Goud Pachimatla
Post-Doctoral Research Affiliate
Roswell park Comprehensive Cancer center
Buffalo, New York, United States
Akhil Goud Pachimatla
Post-Doctoral Research Affiliate
Roswell park Comprehensive Cancer center
Buffalo, New York, United States
Yeshwanth Vedire, MD
Post- Doctoral Research Affiliate
Roswell park comprehensive cancer center, United States
Sukumar Kalvapudi, MD
Post- Doctoral Research Affiliate
Roswell park comprehensive cancer center, United States
kaylan Gee, MD
Post-Doctoral Research Affiliate
Roswell park comprehensive cancer center, United States
Hua-Hsin Hsiao, MD
Biostatistician
Roswell Park Comprehensive cancer center, United States
Todd Demmy, MD
Professor
Roswell Park Comprehensive Cancer Center, United States
Spencer Rosario, PhD
Assistant professor
Roswell Park Comprehensive cancer center, United States
Sai Yendamuri, MD, MBA
Professor and Chair of Thoracic Surgery
Roswell Park Comprehensive Cancer Center
Buffalo, New York, United States
Using both preclinical models and outcome data, we have previously demonstrated that the obesity paradox in NSCLC is an artifact induced by the use of body mass index (BMI) as a measure of obesity. However, the mechanistic basis of the relationship between adiposity and lung cancer behavior is yet to be unraveled. As a starting point, we examined the association of image-based measures of obesity with tumor gene expression.
Methods:
Gene expression data generated as part of the ORIEN project from 143 NSCLC tumors limited to adenocarcinoma and squamous cell carcinoma histologies were collated along with image-based measures of total fat. Total fat area (TFA) was measured at the third lumbar vertebral level from non-contrast CT scan images using SliceOmatic software. Visceral and subcutaneous fat were measured separately and added to get total fat measures. As established measures of TFA do not exist, tumors in the top and bottom tertiles were compared. Using a metabolic analysis pipeline developed and validated by us, we used these gene expression differences to map out alterations in metabolic pathways central to this phenomenon.
Results: Of 53,425 transcripts considered expressed, 1,154 transcripts were differentially expressed (p < 0.05 and logFC > 0.58). Figure 1(A, B) shows a volcano plot highlighting differentially expressed genes as well as the 20 pathways most highly enriched with adiposity, 10 of which were upregulated, and 10 were downregulated. Unsurprisingly, several of these involve metabolic pathways central to normal physiology as well as cancer growth. Utilizing our metabolic pipeline, we found 58 metabolic pathways to be significantly enriched (p < 0.05; Figure 1C) in the high TFA individuals, as compared to the low TFA individuals, some of which are expected in obese individuals (lipids), and some of which were unexpected. The most highly enriched pathways were butanoate metabolism, linoleic acid metabolism, biosynthesis of unsaturated fatty acids, and folate one-carbon metabolism.
Conclusions:
Image-based measures of adiposity are related to significant gene expression changes in NSCLC tumors. We have identified several metabolic vulnerabilities induced by obesity in NSCLC that can be manipulated as new approaches to therapy.