SWI/SNF complex differences promote cellular heterogeneity in rhabdoid tumors

See the article by Panwalkar et al in this issue, pp. 785–796.

Rhabdoid tumors are aggressive infantile tumors with poor survival. In the brain they are designated atypical teratoid rhabdoid tumors (AT/RT) and develop most commonly in the cerebellum, while elsewhere they are known as extra-CNS rhabdoid tumors (eCNS-RT) and often arise in the kidneys. The majority of rhabdoid tumors have a mutation in SWItch/sucrose nonfermentable (SWI/SNF) related matrix associated actin dependent regulator of chromatin subfamily B1 (SMARCB1), while a small proportion with intact SMARCB1 have biallelic inactivating mutations in SMARCA4.¹ These genes form subunits of the SWI/SNF DNA remodeling complex. In this issue, Panwalkar et al begin to unravel how heterogeneous expression of SWI/SNF complex subunits can promote cellular heterogeneity in rhabdoid tumors.²

Indeed, despite being associated with a uniform set of genetic drivers, rhabdoid tumors are microscopically quite heterogeneous, and can contain not just rhabdoid and undifferentiated neuroectodermal cells, but also malignant mesenchymal and/or epithelial tissue. Furthermore, recent large-scale genetic and epigenetic studies have revealed distinct molecular subgroups with unique epigenomic landscapes, clinical phenotypes, and drug responses.^3,4 Laboratory studies designed to improve subgroup-specific therapies for rhabdoid tumors still await clinical translation,^4–6 and we continue to treat all rhabdoid tumors with intensive multimodality that can lead to extensive morbidities but only moderate improvements in survival.⁷ A better understanding of how molecular heterogeneity arises in these tumors is key to developing more targeted therapies to help reduce morbidities and improve survival.

The mammalian SWI/SNF complex contains approximately 15 subunits, and Panwalkar et al focus on how paralog heterogeneity can regulate differentiation, therapeutic response, and immune microenvironment in rhabdoid tumors of the kidney and cerebellum. They begin by mapping patterns of expression in the developing mouse kidney and cerebellum for subunits of the 2 major SWI/SNF complexes, known as Brahma/SWI2-related gene 1–associated factor (BAF) and polybromo-associated BAF (PBAF), and identify variable levels of some paralogs, focusing in particular on actin-like protein (ACTL)6a and ACTL6b. In the kidney, ACTL6a was expressed, while ACTL6b was absent. In the cerebellum, both were expressed, but ACTL6a levels were higher in progenitor cells or the external granular layer, while ACTL6b levels were elevated in differentiated cells. These data support the concept that changing patterns of the BAF complex paralog expression may regulate differentiation in the developing cerebellum.

The authors then look at BAF complex paralog expression in rhabdoid tumors and find heterogeneous expression of ACTL6a/ACTL6b in extra-CNS tumors. Interestingly, these tumors developing in the kidney frequently have signs of neuronal differentiation.⁸ Methylation arrays were used to compare tumors with coexpression of ACTL6a/ACTL6b with those that do not express either paralog, and gene set enrichment analysis of differentially methylated regions revealed significant enrichment of neurodevelopmental related pathways. Tumors with coexpression also expressed neuronal markers by immunohistochemistry, suggesting that aberrant coexpression of ACTL6A and ACTL6B drives neuronal differentiation in a subset of eCNS-RT.

Panwalkar et al next explored how SWI/SNF complex heterogeneity leads to different therapeutic responses and clinical outcomes, focusing on regulation of the immune microenvironment in rhabdoid tumors. Assembly of the PBAF complex occurs after assimilation of ACTL6A, followed by incorporation of polybromo-1 (PBRM1).⁹ PBRM1 expression correlates with ACTL6A expression, and low PBRM1 levels are associated with improved survival. Supervised analysis of gene expression data revealed that tumors with low PBRM1 have increased levels of pro-inflammatory markers and increased immune system signaling pathways. In addition, knockout of PBRM1 in rhabdoid tumor cell models led to decreased expression of immunosuppressive cytokines, and immunohistochemical analysis of rhabdoid tumors revealed increased CD8+ T cells in low PBRM1 tumors. These studies suggest that heterogeneity in the SWI/SNF complex influences the tumor immune microenvironment.

This improved understanding may impact therapy, as preclinical studies have shown that checkpoint inhibitors are especially effective in AT/RT.¹⁰ Perhaps PBRM1 expression can serve as a biomarker for tumors that would respond best to checkpoint inhibitors or other immune therapies. In addition, PBRM1 expression may predict a subset of patients that can benefit from reduction in the intensity of standard therapies, protecting from treatment-associated morbidities while preserving good outcomes.

In summary, Panwalkar et al provide important new insights into how the rhabdoid tumor group, despite their genetically monotonous drivers, can establish molecular, cellular, and phenotypic patterns of heterogeneity. Such studies should improve our understanding of the pathways that drive rhabdoid tumors’ differential response to standard therapies, and help uncover subgroup-specific vulnerabilities that can be targeted to improve survival. Indeed, other preclinical work has begun to suggest strategies to target subgroups of rhabdoid tumors.^4–6 As we build on these important insights into rhabdoid tumor biology, treatments will hopefully become more sophisticated, reducing treatment-associated morbidities and improving survival in rhabdoid tumor patients.

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