The BCL-2 family member BOK promotes KRAS-driven lung cancer progression in a p53-dependent manner.

A variety of cancer entities are driven by KRAS mutations, which remain difficult to target clinically. Survival pathways, such as resistance to cell death, may represent a promising treatment approach in KRAS mutated cancers. Based on the frequently observed genomic deletions of BCL-2-related ovarian killer (BOK) in cancer patients, we explored the function of BOK in a mutant KrasG12D-driven murine model of lung cancer. Using KrasG12D/+ Bok-/- mice, we observed an overall tumor-promoting function of BOK in vivo. Specifically, loss of BOK reduced proliferation both in cell lines in vitro as well as in KrasG12D-driven tumor lesions in vivo. During tumor development in vivo, loss of BOK resulted in a lower tumor burden, with fewer, smaller, and less advanced tumors. Using KrasG12D/+ Tp53Δ/Δ Bok-/- mice, we identified that this phenotype was entirely dependent on the presence of functional p53. Furthermore, analysis of a human dataset of untreated early-stage lung tumors did not identify any common deletion of the BOK locus, independently of the TP53 status or the histopathological classification. Taken together our data indicate that BOK supports tumor progression in Kras-driven lung cancer

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

A step towards valid detection and quantification of lung cancer volume in experimental mice with contrast agent-based X-ray microtomography

Tumor volume is a parameter used to evaluate the performance of new therapies in lung cancer research. Conventional methods that are used to estimate tumor size in mouse models fail to provide fast and reliable volumetric data for tumors grown non-subcutaneously. Here, we evaluated the use of iodine-staining combined with micro-computed tomography (micro-CT) to estimate the tumor volume of ex vivo tumor-burdened lungs. We obtained fast high spatial resolution three-dimensional information of the lungs, and we demonstrated that iodine-staining highlights tumors and unhealthy tissue. We processed iodine-stained lungs for histopathological analysis with routine hematoxylin and eosin (H&amp;E) staining. We compared the traditional tumor burden estimation performed manually with H&amp;E histological slices with a semi-automated method using micro-CT datasets. In mouse models that develop lung tumors with well precise boundaries, the method that we describe here enables to perform a quick estimation of tumorous tissue volume in micro-CT images. Our method overestimates the tumor burden in tumors surrounded by abnormal tissue, while traditional histopathological analysis underestimates tumor volume. We propose to embed micro-CT imaging to the traditional workflow of tumorous lung analyses in preclinical cancer research as a strategy to obtain a more accurate estimation of the total lung tumor burden.</p