Abstract A21: Proteomic profiling to elucidate intratumoral heterogeneity and cancer evolution in lung cancer
Authors: Lee Charlotte , Wu Hua-Jun , Moreira Andre L. , Seeley Erin H. , Walsh Callee , Downey Robert J. , Michor Franziska 
Published: May 2016

Tumors often display a high degree of intratumoral heterogeneity as manifested by dynamic changes in gene expression, protein expression, and on gross examination of histology, among many other features. Clinically, this underlying heterogeneity can drive tumor evolution and progression towards a more aggressive neoplastic state and a worse prognosis for patients; therefore, identifying the diverse composition of a tumor for early risk stratification is of critical importance. To elucidate intratumoral heterogeneity and intracellular hierarchy in a novel manner, we first conducted a low-cost quantitative proteomics analysis using MALDI-TOF mass spectrometry on over 1900 samples from different histological regions of individual tumors from 35 lung cancer patients, as well as from 3 mesenchymal stem cell samples. The histologies identified were acinar, basal cells, bronchial epithelium, lepidic, complex gland, micropapillary, near tumor normal, normal alveolar, papillary, papillary lepidic, papillary mucinous, and solid. Patient-specific information including survival status, sex, age, smoking status, SUV by FDG-PET scan, tumor size, EGFR, KRAS, and ERCC1 mutation status, among other variables was obtained. We then compared the proteomes derived from each tumor to the stem cell proteomes, and using computational strategies, mapped the distance of each histological sample from the mesenchymal stem cell state; using clustering techniques, we organized the major histological subtypes into a phylogenetic tree from stem cells to normal lung. We hypothesized that by applying and improving upon map of tumor evolution based on the distance of each individual histological sample from a stem cell state. Apart from liquid tumors, there have thus far been limited studies on the prognostic significance of different subclones in solid tumors, and therefore we treated each histological sample as a subclone within each patient. We also aimed to identify survival-associated subclones and prognostic molecular signatures across combinations of subclones. Identifying these subclones may provide insight into malignant micrometastases to other organs. Using co-expression network analysis, we further pinpointed distinctive significantly dysregulated co-regulatory protein networks within each histological subtype. Based on these networks, we sought to identify important hub proteins within each histology. Ultimately, using proteomic profiling in solid tumors can be a novel approach in functionally characterizing intratumoral heterogeneity, and may allow for a more robust analysis of the diverse molecular expression of single tumor samples. Our results may help inform the field of targeted broad-scale proteomics profiling for therapeutic use.

Citation Format: Charlotte Lee, Hua-Jun Wu, Andre L. Moreira, Erin H. Seeley, Callee Walsh, Robert J. Downey, Franziska Michor. Proteomic profiling to elucidate intratumoral heterogeneity and cancer evolution in lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A21.