Salem et al. Page 805

The present study characterizes the prevalence of microsatellite instability (MSI), tumor mutation load (TML), and PD-L1 in a large clinical cohort of gastrointestinal tumors. The clinicopathological relationship between these three features offers a more comprehensive understanding of these immune biomarkers, which may enable better patient selection and a more informed therapeutic choice to improve clinical outcome with cancer immunotherapies. These data suggest that TML-high and MSI-high (MSI-H) rates varied widely among gastrointestinal cancers. Although, MSI-H is conceivably the main driver for TML-high tumors other factors (e.g., HPV infection) may be involved.

Yang et al. Page 745

Activation of the IRE1α-XBP1 branch of the unfolded protein response (UPR) has been implicated in various human cancers; however, mechanistic understanding of this activation remains elusive. In this Rapid Impact, by Yang and colleagues, a genome-wide, loss-of-function, luciferase reporter-based siRNA screen was performed to identify genes involved in IRE1α-XBP1 signaling regulation. Pathway analysis uncovered a subset of genes implicated in the pathogenesis of breast cancer. Several genes including BCL10, GCLM, and IGF1R correlated with worse relapse-free survival (RFS) for patients with triple-negative breast cancer (TNBC). The novel genes identified as important for XBP1 activation suggest new therapeutic paradigms for cancers in which the UPR is dysregulated.

Chatterjee et al. Page 791

SWI/SNF is an evolutionarily conserved multi-subunit chromatin remodeling complex that regulates epigenetic architecture and cellular identity. Although SWI/SNF genes are frequently altered in human malignancies, the evidence showing their involvement in tumor cell-autonomous chromatin regulation and transcriptional plasticity is limiting. Rac GTPases play a crucial role in leukemia cell engraftment, however the mechanism of Rac activation in acute myeloid leukemia (AML) is incompletely understood. Here, loss of SMARCB1 in AML associates with SWI/SNFΔ nucleation, which promotes Rac GTPase guanine nucleotide exchange factors expression, Rac activation, migration, and survival of AML cells. Thus, highlighting SWI/SNFΔ downstream signaling as an important molecular regulator in AML.

Bowers et al. Page 869

Obesity is associated with poor prognosis in women with triple-negative breast cancer (TNBC). Bowers and colleagues now demonstrate that increased leptin signaling drives obesity-associated TNBC development by promoting cancer stem cell (CSC) enrichment and epithelial-to-mesenchymal transition (EMT). In a transgenic mouse model of TNBC, obesity reduced tumor-free survival and increased CSC/EMT gene expression, aldehyde dehydrogenase activity, and leptin signaling. Leptin receptor knockdown attenuated the obesity-induced CSC/EMT phenotype and Foxc2, Twist2, Vim, Akt3, and Sox2 expression in TNBC cells. Greater understanding of the leptin-related signals regulating CSC and EMT may reveal new strategies for decreasing TNBC burden in obese women.