Supplement: Systems Biochemistry in Lung Cancer: Toward a Mechanistic Understanding of NSCLC

The present P01 5P01CA163223-04 ¡§Systems Biochemistry in Lung Cancer: Toward a Mechanistic Understanding of NSCLC¡¨ uses stable isotope tracing coupled with metabolic analysis to determine the reprogrammed metabolism in non-small lung cancer, with different model systems including cell culture 1, mouse PDX (patient-derived xenografts) 2, fresh tissue culture (¡§Warburg¡¨ slices)3 4 5 and human subjects in situ 4 5. A major goal is to elucidate the functional role of the tumor microenvironment (TME) on the tumor development, particularly the immune component of the TME, which manipulate with the immunomodulator ƒÒ-glucan to repolarize the tumor macrophages toward the tumoricidal M1-like state 6,7. We have been developing approaches for integrating model system analyses with clinical data, especially with the Warburg tissue slices, which we now consider to be a particularly valuable model system for evaluating tumor biology 5.These slices can be maintained metabolically viable for at least 48 h, sufficient time for testing the acute effects of therapeutics. As we use both cancer and non-cancerous tissues from each patient and the slices retain both the original tissue architecture and the original cell types, we expect that this model will translate more accurately than other preclinical models 5. We have also shown that the lipid composition of exosomes from peripheral blood differs greatly between healthy individuals and those with early stage as well as later stage NSCLC, such that the lipid profile can successfully predict the presence of NSCLC with an accuracy of > 90% (manuscript in preparation). We are presently testing whether the cancerous lipid profile regresses to a ¡§healthy¡¨ signature in response to treatment of the cancer (either resection or chemotherapy), in which case this will be a convenient longitudinal marker of therapeutic response for monitoring purposes. Our preliminary data support the utility of the ex vivo tissue slice approach with stable isotope resolved metabolomics (SIRM) tracing for preclinical applications as well as for studying fundamental tumor biology 3,4,8,9, as have other groups 10,11. Furthermore, this model is necessarily personalized, and we have shown that tissue slices from individuals responded differently to ƒÒ-glucan in 24 h of treatment after tissue resection.