Highlights of This Issue

Osteosarcoma (OS) is a highly aggressive bone tumor of childhood and adolescence for which alternative therapeutic options are urgently needed. Baglio and colleagues demonstrate that osteosarcoma cells release TGFβ-rich extracellular vesicles that educate mesenchymal stem cells to support tumor progression through IL6 secretion. Therapeutic blockade of IL6R prevents lung metastasis formation induced by tumor-educated MSCs in an orthotopic xenograft mouse model of osteosarcoma. OS patients have activated TGFβ and stroma-dependent IL6 signaling and display elevated circulating levels of EV-associated TGFβ. This study provides the basis for the use of IL6 and TGFβ blocking agents as new therapeutic strategy for osteosarcoma.

Robust preclinical models of pediatric acute lymphoblastic leukemia (ALL) are essential in prioritizing novel drugs for clinical evaluation. Jones and colleagues developed bioluminescence imaging (BLI)-enabled ALL patient-derived xenografts (PDXs), and compared BLI with traditional flow cytometric methods in evaluating preclinical drug efficacy. BLI monitored remission with greater range than PB measurements and allowed measurement of leukemia in discrete organs. Correlating BLI and flow cytometry data enabled noninvasive assessment of minimal residual disease, as well as the establishment of novel scoring parameters. This article highlights the utility of BLI in enabling stringent evaluation of drug efficacy in ALL PDXs, ensuring that only the most promising agents are put forward for clinical assessment.

Implementation of primary high-risk HPV testing in cervical screening results in better protection against cervical (pre)cancer. However, its specificity for clinically meaningful disease is lower than that of current cytology-based screening. Therefore, molecular markers that identify clinically relevant lesions would reduce over-referral and overtreatment. Following a genome-wide approach, Verlaat and colleagues identified three novel methylation markers located at a chromosomal gain at 3q, which showed an excellent clinical performance for detection of cervical (pre)cancer in cervical scrapes. These markers enable the detection of advanced precursor lesions with a high short-term progression risk to cancer. These findings could greatly improve cervical screening.

Many Gleason pattern 3 (Gp3) prostate cancers detected on biopsy are indolent and do not require further therapy, but a subset of these patients will have or develop higher-grade cancers. Sowalsky and colleagues establish that a subset of Gp3 tumors emerge early from a common precursor lesion that also can progress to Gp4. These Gp3 tumors have molecular features, including tumor suppressor losses that may distinguish them from indolent Gp3, and which may be used clinically as biomarkers to identify patients with only Gp3 on biopsy who are at increased risk of having occult Gp4.