Prostate cancer is an androgen-dependent disease; therefore, current approaches for treatment aim to disrupt androgen signaling. Unfortunately, this approach is rarely curative due to the selection of resistant clones and adaptation of stromal and endothelial cells to support tumor growth. In this episode, Neil Bhowmick and colleagues evaluated epigenetic alterations in prostate cancer-associated fibroblasts (CAFs) and determined that the Ras inhibitor RASAL3 is silenced in these cells, thereby driving macropinocytosis-mediated glutamine synthesis due to increased oncogenic Ras activity. The increase in stromal glutamine associated with neuroendocrine differentiation, and in prostate cancer patients, blood glutamine levels were elevated in patients that were resistant to androgen deprivation compared to those that were responsive. Together, these results suggest that strategies to prevent glutamine uptake be considered in conjunction with androgen deprivation.
Upwards of 10% of all bone fractures fail to heal properly, with dysfunctional repair even more common in individuals with metabolic defects. Vitamin D has been implicated in fracture healing, which involves formation of a soft callus at the fracture site that is later mineralized and ossified. In this episode, René St-Arnaud and colleagues determined that that ossification is impaired in Cyp24a1-deficient mice, which are unable to synthesize the vitamin D metabolite 24R,25-dihydroxyvitamin D3, following traumatic bone injury. FAM57B2 was upregulated in the fracture callus of Cyp24a1-deficient mice and an interaction between FAM57B2 and 24R,25-dihydroxyvitamin D3 in chondrocytes produced lactosylceramide, which supports callus mineralization. Importantly, lactosylceramide supplementation improved mineralization in both Cyp24a1- and Fam57b2-deficient calluses, suggesting that this 24R,25-dihydroxyvitamin D3–dependent pathway has potential to be targeted to optimize bone repair after fracture.
Podocyte dysfunction is a hallmark of kidney injury and occurs in both autoimmune and nonautoimmune renal diseases. Calcium signaling underlies podocyte injury; however, the factors that promote calcium signaling in podocytes in response to injury are not fully understood. In this episode, George Tsokos and colleagues demonstrate that Ca2+/calmodulin–dependent kinase 4 (CaMK4) is increased in podocytes from patients with lupus nephritis and focal segmental glomerulosclerosis and in mouse models of lupus and kidney injury. Moreover, administration of a CaMK4 inhibitor prevented nephritis in lupus-prone mice and ameliorated podocyte damage in mice with kidney injury. Togeither, this study identifies CaMK4 activation as a driver of podocyte dysfunction and suggests CaMK4 inhibition be further explored for treating podocytopathies.
How are behavioral decisions modified by context and experience? Cornelia Bargmann of Rockefeller University has made this her life’s work, exploring the intersection between genes, the environment, and the nervous system in the roundworm, C. elegans. Bargmann is also seeking to help cure, manage, and prevent all disease by the year 2100 by serving as Head of Science for the Chan Zuckerberg Initiative.
Prostate cancer is driven by stimulation of the androgen receptor (AR) with testosterone and the potent metabolite 5α-dihydrotestosterone; therefore, androgen deprivation, via medical or surgical castration, is the standard treatment for disease. Unfortunately, extragonadal androgen production often increases in response to castration. In particular, patients with a 1245A>C variant of HSD3B1, which encodes 3β-hydroxysteroid dehydrogenase-1(3βHSD1), exhibit rapid development of castration resistance. In this episode, Nima Sharifi and colleagues evaluated the effect of the HSD3B1(1245C) variant on metabolism of abiraterone, a drug used to block extragonadal androgens. Compared to those with HSD3B1(1245A), those with the mutation had increased levels of the metabolite 3-keto-5α-abiraterone, which has androgenic activity. These results support further investigation into the clinical consequences of increased 3-keto-5α-abiraterone in patients harboring HSD3B1(1245C).