Dissecting the interplay between aging, genotype and the microenvironment in lung cancer

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PROJECT SUMMARY Cancer is primarily a disease of the old. While this is due in part to the sequential acquisition of genomic alterations, aging is also associated with a constellation of changes that could impact tumor initiation and growth. These “hallmarks of aging” involve diverse pathways that impinge on carcinogenesis and lead to systemic changes. However, despite the very close association between aging and cancer, or perhaps because of it, very little is known about how cancer cell-intrinsic, microenvironmental, and systemic age-related changes impact cancer initiation and growth. Genetically engineered mouse models uniquely enable the introduction of defined genetic alterations into normal adult cells with defined temporal control. Human lung cancer has been modeled using genetically engineered mouse models, and these tumors recapitulate many features of early-stage human lung adenocarcinoma. To increase the scope and precision of in vivo cancer modeling, we integrated conventional genetically engineered mouse models, CRISPR/Cas9-based somatic genome engineering, and quantitative genomics with statistical approaches. Tumor barcoding coupled with CRISPR/Cas9-mediated gene inactivation and high-throughput barcode sequencing (Tuba-seq) enables quantitative analysis of the effects of large panels of genes on tumor initiation and various facets of autochthonous tumor growth. These models can thus distinguish the effects of aging from mutational events while affording a level of precision that allows us to detect differences in tumor suppressor function across age contexts. In Aim 1, we will quantify the interaction between age and tumor suppressor gene function. Our in vivo experiments will define whether aging increases or decreases the absolute efficiency of tumor initiation and uncover the impact of aging on the importance of diverse tumor suppressor genes on tumor initiation and growth. In Aim 2. we will determine how the lung tumor microenvironment and lung cancer cells themselves change with age. We will elucidate the impact of tumor genotype on the microenvironment across age and determine whether age-dependent changes in growth are accompanied by dramatic differences in cancer cell state. In Aim 3, we will disentangle cell-autonomous differences in tumors developing in young and aged mice from effects on tumor suppressor function driven specifically by aging of the local tissue and systemic host environments. These experiments will provide insight into whether age-dependent genotype-specific effects are largely cancer cell-intrinsic or driven by the shifts in the microenvironment or whole organism environment. By permuting cancer cell age and genotype, as well as microenvironment and host age, we will gain an unprecedented understanding of the contribution of these factors to multiple aspects of lung carcinogenesis. Ultimately, these findings could have important implication for cancer prevention, detection, and treatment.