SNAIL1 has been suggested to regulate breast cancer metastasis based on analyses of human breast tumor transcriptomes and experiments using cancer cell lines and xenografts. However, in vivo genetic experimental support for a role for SNAIL1 in breast cancer metastasis that develops in an immunocompetent tumor microenvironment has not been determined. To address this question, we created a genetic SNAIL1 model by coupling an endogenous SNAIL1 reporter with an inducible SNAIL1 transgene. Using multiple genetic models of breast cancer, we demonstrated that endogenous SNAIL1 expression was restricted to primary tumors that ultimately disseminate. SNAIL1 gene deletion either during the premalignant phase or after primary tumors have reached a palpable size blunted metastasis, indicating that late metastasis was the main driver of metastasis and that this was dependent on SNAIL1. Importantly, SNAIL1 expression during breast cancer metastasis was transient and forced transient, but not continuous, SNAIL1 expression in breast tumors was sufficient to increase metastasis.

Standard and targeted cancer therapies for late-stage cancer patients almost universally fail due to tumor heterogeneity/plasticity and intrinsic or acquired drug resistance. We used the telomerase substrate nucleoside precursor, 6-thio-2′-deoxyguanosine (6-thio-dG), to target telomerase-expressing non–small cell lung cancer cells resistant to EGFR-inhibitors and commonly used chemotherapy combinations. Colony formation assays, human xenografts as well as syngeneic and genetically engineered immune competent mouse models of lung cancer were used to test the effect of 6-thio-dG on targeted therapy– and chemotherapy-resistant lung cancer human cells and mouse models. We observed that erlotinib-, paclitaxel/carboplatin-, and gemcitabine/cisplatin-resistant cells were highly sensitive to 6-thio-dG in cell culture and in mouse models. 6-thio-dG, with a known mechanism of action, is a potential novel therapeutic approach to prolong disease control of therapy-resistant lung cancer patients with minimal toxicities.

No abstract

Truncated APC selective inhibitor-1 (TASIN-1) is a recently identified small molecule that selectively kills colorectal cancer cells that express truncated adenomatous polyposis coli (APC) by reducing cellular cholesterol levels. However, the downstream mechanism responsible for its cytotoxicity is not well understood. In this study, we show that TASIN-1 leads to apoptotic cell death via inducing ER stress-dependent JNK activation in human truncated APC colon cancer cells, accompanied by production of reactive oxygen species (ROS). In addition, TASIN-1 inhibits AKT activity through a cholesterol-dependent manner. Human colon tumor xenografts in immunodeficient mice also show the same TASIN-1 induced molecular mechanisms of tumor cell death as observed Taken together, cholesterol depletion by TASIN-1 treatment induces apoptotic cell death through activating ER stress/ROS/JNK axis and inhibiting AKT pro-survival signaling in colon cancer cells with truncated APC both and .

Most of the research in understanding space radiation-induced cancer progression and risk assessment has been performed using mono-energetic single-ion beams. However, the space radiation environment consists of a wide variety of ion species with a various range of energies. Using the fast beam switching technology developed at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), ion species can be switched rapidly allowing investigators to use multiple ions with different energies to simulate more closely the radiation environment found in space. Here, we exposed a lung cancer susceptible mouse model (Kras LA−1 ) to three sequential ion beams: Proton (H) (120 MeV/n) 20 cGy, Helium (He) (250 MeV/n) 5.0 cGy, and Silicon (Si) (300 MeV/n) 5.0 cGy with a dose rate of 0.5 cGy/min. Using three ion beams we performed whole body irradiation with a total dose of 30 cGy in two different orders: 3B-1 (H→He→Si) and 3B-2 (Si→He→H) and used 30 cGy H single-ion beam as a reference. In this study we show that whole-body irradiation with H→He→Si increases the incidence of premalignant lesions and systemic oxidative stress in mice 100 days post-irradiation more than (Si→He→H) and H only irradiation. Additionally, we observed an increase in adenomas with atypia and adenocarcinomas in H→He→Si irradiated mice but not in (Si→He→H) or H (30 cGy) only irradiated mice. When we used the H→He→Si irradiation sequence but skipped a day before exposing the mice to Si, we did not observe the increased