ATF4-SCD axis in bone metastatic prostate cancer

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Project Summary Bone metastatic disease correlates with increased morbidity and mortality in prostate cancer (PCa) patients. Various studies, including our own, have determined that the bone marrow niche plays a supportive role during metastatic progression, which leads to increased tumor cell survival and escape from therapy, but the molecular mechanisms are not fully understood. Our previous studies have highlighted adipocytes, an abundant cell type in the bone marrow, as key modulators of tumor cell energetics and contributors to their aggressive phenotype. We have demonstrated that adipocyte-supplied lipids, released upon adipocyte-tumor cell crosstalk, induce pro- survival phenotype and promote ER and oxidative stress activation as potential cell adaptation mechanisms in PCa cells. My new preliminary data have now uncovered novel molecular consequences of tumor cell-adipocyte crosstalk, including the following: 1) Activation of an adaptive response to lipid peroxidation in PCa cells is mediated by adipocyte-supplied lipids; 2) Augmented expression of ER stress gene, ATF4, and lipid desaturation enzyme, SCD, in PCa cells is a possible defense mechanism against damaging effects of lipid peroxidation; 3) ER stress gene, ATF4, plays a potential role in regulating SCD levels and activity in PCa cells grown under lipid- rich conditions; and 4) Adipocyte-supplied lipids are likely involved in regulating the tumor metabolome. Stemming from these findings, the central hypothesis of this proposal is that adipocyte activation of the ATF4- SCD axis modulates tumor metabolism to promote the survival of PCa in bone. I propose a multi-faceted approach that includes cell culture and mouse models of lipolysis, in vivo models of intratibial tumor growth, as well as state-of-the-art RNAseq and metabolomics approaches to determine the role of previously unexplored ATF4-SCD axis in regulating tumor metabolism and promoting progression in bone. These studies will be performed in two aims. In Aim 1, I will utilize mice deficient in lipolysis and create human and murine PCa cells with stable knockdown of ATF4 to study the role of adipocyte-supplied lipids in modulating the ATF4-ER stress response pathway to promote progression in bone. In Aim 2, I will focus on the ATF4-SCD interaction and utilize RNA-seq and metabolomics approaches to determine how lipid-mediated activation of this axis alters tumor metabolome. Altogether, the results of this study will be used to delineate key molecular mechanisms by which metastatic PCa cells engage ATF4 and SCD to survive in the lipid-rich bone marrow. This work will also likely reveal potential novel options for targeting tumor metabolism for improved therapy and/or prevention of aggressive disease. This proposed work will have broad implications for numerous cancer types that metastasize to bone or those that arise from bone and are likely to be affected by the bone marrow adipose tissue.