Highlights of This Issue

Abstract

Antiendocrine therapy remains the most effective treatment for ER+ breast cancer, but development of resistance is a major clinical complication. Attempts to uncover and therapeutically target mechanisms of antiendocrine resistance have focused mainly on tumor-intrinsic traits. Brechbuhl and colleagues identify two subtypes of cancer-associated fibroblasts (CAFs) based on their CD146 expression. The authors show that CAF subtypes differentially contribute to tumoral ER expression and tamoxifen sensitivity. CD146− CAFs enforce ER-independent growth and mediate tamoxifen resistance by activating receptor tyrosine kinase pathways. Additionally, the CAF subtypes predict treatment response and patient outcomes. These findings have clinical implications that could influence personalized care and support a direct role for the tumor microenvironment in modulating response to antiendocrine therapy.The influence of the TCR repertoire in patients with lymphoma is currently unknown. Keane and colleagues performed TCR sequencing of diagnostic biopsies in a large cohort of patients with DLBCL treated with frontline R-CHOP chemoimmunotherapy. Patients with high frequency of dominant clones had inferior outcomes compared with patients with a more diverse T-cell repertoire. The poor prognosis EBV-associated DLBCL subtype demonstrated significantly higher levels of clonality. These findings indicate that the TCR repertoire in lymphoma biopsies is prognostic and will be an important consideration in future trials using immune checkpoint therapies in this disease.The CXCR4/CXCL12 chemokine axis plays an important role in multiple myeloma (MM) pathophysiology. The sphingosine-1-phosphate (S1P) pathway is considered to be involved in MM pathogenesis. In this study, Beider and colleagues describe potent in vitro and in vivo anti-MM effects of the S1P modulator FTY720. CXCR4 is identified as a molecular target of FTY720, suggesting functional cross-talk between CXCR4 and S1P pathways in MM. They demonstrate the ability of FTY720 to cooperate with bortezomib and target MM cells in the bone marrow niche using a novel in vivo xenograft model of CXCR4-driven MM that recapitulate the natural BM milieu. This work provides a model to study novel anti-MM agents and a rationale for therapeutic application of FTY720 in MM.Pituitary adenomas are the second-most common primary brain tumor, yet their genetic profiles are incompletely understood. Bi and colleagues demonstrate a statistically significant association between genetic determinants (degree of chromosomal disruption) and the corresponding phenotype (functional adenomas) in pituitary tumors. The authors validated this association between genomic disruption and functional subtype in two additional sample sets and found that the alterations also affect gene-expression levels. They observed no significantly recurrent mutations across this cohort of macroadenomas, suggesting that a single driver gene is unlikely to be mutated in a substantial fraction of pituitary macroadenomas, and by extension, that no single targeted therapy is likely to be effective against large fractions of pituitary tumors. The data enable a more systematic, genetic basis for the classification and treatment of pituitary tumors.