Pressured to Move
Lobopodia, migration characterized by blunt, cylindrical protrusions and lateral blebs, occurs in highly cross-linked three-dimensional matrices that mimic extracellular matrices of cancer. Petrie and colleagues show that migrating primary human fibroblasts in a three-dimensional collagen matrix with lobopodia had high intracellular pressures (∼2,200 Pa) as compared with cells with lamellipodia (∼700 Pa). Actomyosin contractility was required to maintain these high pressures, with the nucleus dividing the cell into a high-pressure anterior compartment and a low-pressure posterior compartment. This pressure differential and the lobopodial protrusions required nesprin-3 (SYNE3), a nucleoskeleton-vimentin linker protein important in polarity and migration. Thus, the nucleus acts as a piston to pressurize the anterior cytoplasmic compartment and drive lobopodial protrusions and directional migration. An understanding of the mechanisms driving migration promises to enhance our ability to inhibit migration in cancer.
Molecular Characterization of Gastric Adenocarcinoma
Gastric cancer is the third most lethal cancer. Existing classification systems have limited clinical utility, leading The Cancer Genome Atlas to profile 295 primary gastric adenocarcinomas for somatic copy number; DNA methylation; protein binding; and whole-genome, RNA, and microRNA sequencing. Cancers were segregated into four distinct subtypes, based on Epstein-Barr virus positivity, microsatellite instability, genomic stability, and chromosomal instability. Although the four subtypes localized differentially within the stomach, presented at distinct ages, and differed in frequency between men and women, the subgroups did not differ in survival. Importantly, numerous druggable targets segregated into each subtype of gastric cancer, which could influence future clinical trials.
Imaging Prostate Cancer Using the AEG-1 Promoter
No reliable imaging agent is currently available for detecting metastatic prostate cancer. Bhatnagar and colleagues identify a novel imaging method for detection of localized and metastatic prostate cancer. The method involves placement of an imaging reporter gene under the transcriptional control of a cancer-selective promoter from astrocyte elevated gene-1 (Metadherin, MTDH), AEG-1 promoter. Nanoparticles containing the imaging construct were delivered systemically, and tumor lesions were visualized using bioluminescent imaging and single photon emission–computed tomography in a murine model of prostate cancer. Prostate cancer metastases to regions such as the bone were detectable with this imaging method. This type of imaging is comparable with accepted and emerging clinical standards for tumor detection. Bhatnagar and colleagues have provided preclinical proof-of-concept, and their findings may have clinical relevance for detecting tumors in patients with advanced prostate cancer, including imaging of bone metastases.
Endocytic Motors of Metastasis
The GTPase RAB5A functions in early endosomes to regulate traffic of cell surface cargo proteins including receptor tyrosine kinases and integrins. RAB5A overexpression was correlated with poor prognosis in breast cancer, and levels were increased in lymph node metastases relative to primary tumor from the same patient. Thus, high RAB5A levels were correlated with tumor cell dissemination. Importantly, dominant-negative RAB5A impaired lung extravasation and distant metastasis in mice inoculated with basal-like breast cancer cells. In vitro, RAB5A was necessary for formation of degradative actin-rich invadosomes and cell invasion into three-dimensional collagen matrices. Mechanistically, RAB5A promoted RAB4-dependent fast recycling of membrane-type metalloprotease and αvβ3-integrin to drive localized formation of invadosomes and invasion. Thus, the ability of RAB5A to couple migratory and invasive protrusions is clinically relevant for dissemination and correlated with breast cancer aggressiveness in patients.
TCGA Pan-Cancer Analysis Refines Tumor Classification
The Cancer Genome Atlas research network performed integrative analysis on mRNA, microRNA, DNA copy number, DNA methylation, and protein expression on 3,527 tumors. They identified 13 clusters, 11 of which included more than 10 samples. Of these 11 clusters, 5 showed one-to-one relationships with the tissue site of origin: clear cell carcinoma of the kidney, endometrial carcinoma, ovarian carcinoma, glioblastoma, and acute myelogenous leukemia. A sixth group was ∼80% non–small cell lung carcinoma. Among the other 5 tissue types, breast cancer diverged into estrogen receptor–positive plus HER2 (ERBB2)-positive tumors, and triple-negative basal-like tumors. Squamous carcinomas of the head and neck converged with squamous carcinoma of the lung. Bladder cancers showed 3 groups, only one of which was primarily bladder cancer. Molecular subgroups provide survival information beyond that available from clinicopathologic parameters, offering a framework for molecular classification with relevance to the clinic.
Restoring Tumor Growth Inhibitory Signals in the Stroma
How ephrins and their receptor tyrosine kinases, Ephs, regulate tumor growth is still unclear. Vail and colleagues show that EPHA3 is expressed in a specific subset of bone marrow–derived mesenchymal myeloid and stromal cells in the tumor microenvironment of a broad range of human and mouse tumors. Treatment with an EPHA3-activating mAb IIIA4 led to EPHA3 signaling and rapid tumor cell apoptosis. Tumor growth was inhibited significantly. The architecture of the tumor stroma and microvasculature were destabilized, supporting the notion that multiple host-derived signals can antagonize tumor growth. The study further reveals that restoration of EPHA3 signaling in the stroma could cooperate with cancer cell–specific drugs to accelerate regression and to prevent the persistence of a stroma conducive for residual tumor cell survival and recurrence.
Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.
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