Serpins promote cancer cell survival and vascular co-option in brain metastasis.

Brain metastasis is an ominous complication of cancer, yet most cancer cells that infiltrate the brain die of unknown causes. Here, we identify plasmin from the reactive brain stroma as a defense against metastatic invasion, and plasminogen activator (PA) inhibitory serpins in cancer cells as a shield against this defense. Plasmin suppresses brain metastasis in two ways: by converting membrane-bound astrocytic FasL into a paracrine death signal for cancer cells, and by inactivating the axon pathfinding molecule L1CAM, which metastatic cells express for spreading along brain capillaries and for metastatic outgrowth. Brain metastatic cells from lung cancer and breast cancer express high levels of anti-PA serpins, including neuroserpin and serpin B2, to prevent plasmin generation and its metastasis-suppressive effects. By protecting cancer cells from death signals and fostering vascular co-option, anti-PA serpins provide a unifying mechanism for the initiation of brain metastasis in lung and breast cancers.

Unbiased compound screening identifies unexpected drug sensitivities and novel treatment options for gastrointestinal stromal tumors.

Most gastrointestinal stromal tumors (GIST) are caused by oncogenic KIT or platelet-derived growth factor receptor activation, and the small molecule kinase inhibitor imatinib mesylate is an effective first-line therapy for metastatic or unresectable GIST. However, complete remissions are rare and most patients ultimately develop resistance, mostly because of secondary mutations in the driver oncogenic kinase. Hence, there is a need for novel treatment options to delay failure of primary treatment and restore tumor control in patients who progress under therapy with targeted agents. Historic data suggest that GISTs do not respond to classical chemotherapy, but systematic unbiased screening has not been performed. In screening a compound library enriched for U.S. Food and Drug Administration (FDA)-approved chemotherapeutic agents (NCI Approved Oncology Drugs Set II), we discovered that GIST cells display high sensitivity to transcriptional inhibitors and topoisomerase II inhibitors. Mechanistically, these compounds exploited the cells' dependency on continuous KIT expression and/or intrinsic DNA damage response defects, explaining their activity in GIST. Mithramycin A, an indirect inhibitor of the SP1 transcription factor, and mitoxantrone, a topoisomerase II inhibitor, exerted significant antitumor effects in mouse xenograft models of human GIST. Moreover, these compounds were active in patient-derived imatinib-resistant primary GIST cells, achieving efficacy at clinically relevant concentrations. Taken together, our findings reveal that GIST cells have an unexpectedly high and specific sensitivity to certain types of FDA-approved chemotherapeutic agents, with immediate implications for encouraging their clinical exploration.

The failure response of the human cervical facet capsular ligament during facet joint retraction.

Studies implicate the cervical facet joint and its capsule as a primary anatomical site of injury during whiplash exposures to the neck. Although the facet joint is known to undergo stretch as the superior vertebra is retracted relative to the inferior vertebra during the whiplash kinematic, the response of the facet capsular ligament and its microstructure during failure in joint retraction is unknown. Polarized light imaging and vector correlation analysis were used to measure the collagen fiber alignment in the human capsular ligament, together with traditional mechanical metrics, during joint retraction sufficient to induce ligament failure. Anomalous fiber realignment occurs at 2.95±1.66mm of displacement, which is not different from the displacement when the ligament first yields (2.77±1.55mm), but is significantly lower (p=0.016) than the displacement at tissue failure (5.40±1.65mm). The maximum principal strain at the first detection of anomalous fiber realignment (0.66±0.39) also is significantly lower (p=0.046) than the strain at failure (1.39±0.64), but is not different from the strains at yield or partial failure. The onset of collagen fiber realignment determined in this study corresponds to the ligament's yielding and supports assertions that the facet capsule can undergo tissue injury during joint retraction. Further, such microstructural responses may indicate tissue damage in the absence of rupture.