Abstract 5109: ATF4 and SCD: Co-conspirators in promoting the progression of metastatic prostate cancer in bone

Prostate Cancer (PCa) is predisposed to metastasize to bone, a hospitable environment abundant in adipocytes. Our previous studies have highlighted the critical role of marrow adipocytes in PCa progression and chemoresistance in bone. Bone marrow adipocytes are metabolic cells that interact with neighboring cells through the secretion of lipids and adipokines. Specifically, we have shown that interaction with adipocytes promotes lipid uptake by PCa cells and activates ER/oxidative stress pathways; however, the mechanisms behind the tumor-promoting effects of adipocytes are not clearly understood. The main objective of this study was to investigate the molecular mechanisms underlying lipid-induced stress during tumor cell-adipocyte crosstalk and its functional relationship to tumor progression in bone. Previously, we have demonstrated that adipocyte exposure increases expression of lipogenic enzyme stearoyl-CoA desaturase (SCD) and ER stress regulator ATF4 in PCa cells. Here, we show that SCD expression decreases with transient knockdown of ATF4. Also, through dual transient knockdown of SCD and ATF4, we determine that SCD deficiency leads to an increase of ER stress genes and demise of PCa cells only when expression of ATF4 is present. We also observe this phenomenon in PCa cells with a stable knockdown of ATF4 (shATF4), suggesting an interplay between SCD and ATF4. Additionally, we reveal that shATF4 PCa cells have decreased proliferation in vitro, reduced ER stress signaling, and increased lipid peroxidation levels. RNAseq analyses of shATF4 cells demonstrate the downregulation of inflammation-related pathways, such as NFkB. Notably, we observe that shATF4 cells have decreased expression of protein tyrosine phosphatase receptor type D (PTPRD) compared to control cells. PTPRD has been implicated in regulating inflammatory pathways but, to our knowledge, has not been shown to be regulated by ATF4. Curiously, shATF4 cells that undergo knockdown of SCD cannot induce pathways involved in apoptotic signaling and ER stress signaling compared to control cells with SCD knockdown. We also observe the induction of the NOTCH signaling pathway and increased expression of p53 apoptosis effector (PERP), a gene regulated directly by NOTCH, in shATF4 cells grown in co-culture with adipocytes. This is in contrast to control cells with SCD knockdown, where we observe a decrease in PERP expression. These results indicate that the downregulation of inflammatory pathways during ATF4 knockdown may be occurring through PTPRD. Also, the increase in NOTCH signaling, which may be due to the reciprocal activation of NFkB and NOTCH pathways, may be counteracting the anti-tumor effects of SCD inhibition on PCa cells. Overall, we demonstrate an interplay between ATF4 and SCD and the critical role of ATF4 in mediating the anti-tumor effects of SCD, which may have therapeutic complications for bone metastatic PCa. Citation Format: Alexis R. Wilson, Shane Mecca, Mackenzie Herroon, Shrila Rajendran, Laimar Garmo, Izabela Podgorski. ATF4 and SCD: Co-conspirators in promoting the progression of metastatic prostate cancer in bone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5109.