SMARCB1 regulates the hypoxic stress response in sickle cell trait

Abstract

Renal medullary carcinoma (RMC) is an aggressive kidney cancer that almost exclusively develops in individuals with sickle cell trait (SCT) and is always characterized by loss of the tumor suppressor SMARCB1 . Because renal ischemia induced by red blood cell sickling exacerbates chronic renal medullary hypoxia in vivo, we investigated whether the loss of SMARCB1 confers a survival advantage under the setting of SCT. Hypoxic stress, which naturally occurs within the renal medulla, is elevated under the setting of SCT. Our findings showed that hypoxia-induced SMARCB1 degradation protected renal cells from hypoxic stress. SMARCB1 wild-type renal tumors exhibited lower levels of SMARCB1 and more aggressive growth in mice harboring the SCT mutation in human hemoglobin A (HbA) than in control mice harboring wild-type human HbA. Consistent with established clinical observations, SMARCB1-null renal tumors were refractory to hypoxia-inducing therapeutic inhibition of angiogenesis. Further, reconstitution of SMARCB1 restored renal tumor sensitivity to hypoxic stress in vitro and in vivo. Together, our results demonstrate a physiological role for SMARCB1 degradation in response to hypoxic stress, connect the renal medullary hypoxia induced by SCT with an increased risk of SMARCB1-negative RMC, and shed light into the mechanisms mediating the resistance of SMARCB1-null renal tumors against angiogenesis inhibition therapies.

Update on Selected High-grade Renal Cell Carcinomas of the Kidney: FH-deficient, ALK-rearranged, and Medullary Carcinomas

“…Interestingly, applying single-cell technology in a small number of RMC cases, a couple of recent studies identify tumor cell populations with gene expression signatures suggestive of a cell-of-origin from the thick ascending limb of the loop of Henle 56,57 . Overall, recent mechanistic studies suggest that loss of SMARCB1 promotes cell survival and transformation in response to extreme hypoxia or the high extracellular iron levels in the medulla of sickle cell trait patients 56–58 …”

The Role of Sampling in Medicine

“…develop new therapies and understand how and why renal medullary carcinoma (RMC) occurs in certain populations (Shapiro et al, 2021;Soeung et al, 2023). RMC is a deadly kidney cancer that mainly afflicts young individuals carrying the sickle cell trait, an inherited blood disorder that otherwise typically has minimal health impact (Msaouel et al, 2019).…”

A Phase II Clinical Trial of Pembrolizumab Efficacy and Safety in Advanced Renal Medullary Carcinoma

“…First described as a distinct entity in 1995 [1], renal medullary carcinoma (RMC) is a rare type of kidney cancer that afflicts almost exclusively young patients with a sickle cell hemoglobinopathy, usually of African descent [2][3][4]. RMC is characterized by the loss of the SMARCB1 protein (also known as INI-1, hSNF5, or BAF47).…”

“…RMC is characterized by the loss of the SMARCB1 protein (also known as INI-1, hSNF5, or BAF47). SMARCB1 is a subunit of the Switch/Sucrose Non-Fermentable (SWI/SNF) complex, a tumor suppressor that is a mediator of chromatin remodeling and modulates transcriptional activity [4][5][6][7][8]. Although RMC comprises less than 0.5% of all RCC cases [9], it is the third-most-common kidney malignancy among adolescents and young adults [6] and is highly aggressive, with less than 5% of patients surviving longer than 36 months on current therapies [10,11].…”

“…Platinum-based cytotoxic chemotherapy is the mainstay of RMC therapy, with a 29% objective response rate noted in a multicenter retrospective study, with only 13% of patients surviving longer than 2 years [10]. RMC has shown a lack of response to vascular endothelial growth factor (VEGF)-directed multi-tyrosine kinase inhibitors (TKIs) and mTOR inhibitors, as well as to other targeted therapies that are used to treat common RCCs subtypes [4,13,14]. Because of the aggressive nature of this disease and poor outcomes, there is great need for new therapeutic strategies [8,[15][16][17].…”