Cross-talk between tumor cells and their microenvironment is critical for malignant progression. Cross-talk mediators, including soluble factors and direct cell contact, have been identified, but roles for the interaction of physical forces between tumor cells and the bone microenvironment have not been described. Here, we report preclinical evidence that tumor-generated pressure acts to modify the bone microenvironment to promote the growth of prostate cancer bone metastases. Tumors growing in mouse tibiae increased intraosseous pressure. Application of pressure to osteocytes, the main mechanotransducing cells in bone, induced prostate cancer growth and invasion. Mechanistic investigations revealed that this process was mediated in part by upregulation of CCL5 and matrix metalloproteinases in osteocytes. Our results defined the critical contribution of physical forces to tumor cell growth in the tumor microenvironment, and they identified osteocytes as a critical mediator in the bone metastatic niche. Cancer Res; 75(11); 1–8. ©2015 AACR.

Elucidating mechanisms of hepatitis B virus (HBV)–mediated hepatocarcinogenesis is needed to gain insights into the etiology and treatment of liver cancer. Cells where HBV is replicating exhibit increased expression of Plk1 kinase and reduced levels of two transcription repression factors, SUZ12 and ZNF198. SUZ12 is an essential subunit of the transcription repressive complex PRC2. ZNF198 stabilizes the transcription repressive complex composed of LSD1, Co-REST, and HDAC1. These two transcription repressive complexes are held together by binding the long noncoding RNA HOTAIR. In this study, we linked these regulatory events mechanistically by showing that Plk1 induces proteasomal degradation of SUZ12 and ZNF198 by site-specific phosphorylation. Plk1-dependent ubiquitination of SUZ12 and ZNF198 was enhanced by expression of HOTAIR, significantly reducing SUZ12 and ZNF198 stability. In cells expressing the HBV X protein (HBx), downregulation of SUZ12 and ZNF198 mediated global changes in histone modifications. In turn, HBx-expressing cells propagated an altered chromatin landscape after cell division, as exemplified by changes in histone modifications of the EpCAM promoter, a target of PRC2 and LSD1/Co-REST/HDAC1 complexes. Notably, liver tumors from X/c-myc bitransgenic mice exhibited downregulation of SUZ12 and ZNF198 along with elevated expression of Plk1, HOTAIR, and EpCAM. Clinically, similar effects were documented in a set of HBV-related liver tumors consistent with the likelihood that downregulation of SUZ12 and ZNF198 leads to epigenetic reprogramming of infected hepatocytes. Because both Plk1 and HOTAIR are elevated in many human cancers, we propose that their combined effects are involved in epigenetic reprogramming associated broadly with oncogenic transformation. Cancer Res; 75(11); 1–12. ©2015 AACR.

This report delivers a comprehensive genetic alteration profile of lung adenocarcinomas (LADC) driven by ALK, RET, and ROS1 oncogene fusions. These tumors are difficult to study because of their rarity. Each drives only a low percentage of LADCs. Whole-exome sequencing and copy-number variation analyses were performed on a Japanese LADC cohort (n = 200) enriched in patients with fusions (n = 31, 15.5%), followed by deep resequencing for validation. The driver fusion cases showed a distinct profile with smaller numbers of nonsynonymous mutations in cancer-related genes or truncating mutations in SWI/SNF chromatin remodeling complex genes than in other LADCs (P < 0.0001). This lower mutation rate was independent of age, gender, smoking status, pathologic stage, and tumor differentiation (P < 0.0001) and was validated in nine fusion-positive cases from a U.S. LADCs cohort (n = 230). In conclusion, our findings indicate that LADCs with ALK, RET, and ROS1 fusions develop exclusively via their dependence on these oncogene fusions. The presence of such few alterations beyond the fusions supports the use of monotherapy with tyrosine kinase inhibitors targeting the fusion products in fusion-positive LADCs. Cancer Res; 75(11); 1–8. ©2015 AACR.

Cell aggregation is frequently impaired during the growth of primary tumors and the formation of metastatic lesions. Cell aggregation depends on cell–cell adhesion; however, no rigorous approach exists to monitor and quantify it accurately in the absence of the confounding factors of cell–substrate adhesion and the resulting cell motility on the substrate. We report here a highly reproducible, automated, microscopy-based quantification of tumor-cell spheroid formation in the absence of cell–substrate adhesion and use it to characterize cell aggregation dynamics in the early steps of this process. This method is based on fluorescence and bright-field microscopy and on a custom MATLAB program to quantify automatically the cells’ aggregation kinetics. We demonstrate that the cell–cell adhesion protein E-cadherin and the desmosome proteins DSG2 and DSC2 are important for aggregation. Furthermore, we show that inhibition or silencing of myosin IIa enhances aggregation, suggesting that cytoskeleton tension inhibits tumor cell aggregation. This work opens new avenues to study the principles that govern multicellular aggregation, to characterize the aggregation properties of various tumor cell types, as well as to screen for drugs that inhibit or promote aggregation. Cancer Res; 75(12); 1–8. ©2015 AACR.

The 25th Annual Komen Philadelphia Race for the Cure® is a Mother’s Day tradition benefiting breast cancer research, education, screening and treatment.

The Penn Medicine Breast Health Initiative (PMBHI) was recently awarded $100,000 from the Susan G. Komen Philadelphia Community Grants Program to provide screening and diagnostic services to an additional 600 women this year.

Twenty-five percent of the funds raised by Komen Philadelphia supports the Komen national research program–a peer reviewed cancer research program offering grants in areas such as diagnosis, treatment, public health, survivorship and prevention. The remainder of the funds raised are invested locally in programs like the PMBHI, which help provide access to care and education in our community – both enriching and saving lives.

These are just a few good reasons to come out and join the Penn Medicine Team.

Interested in joining our team?

To join the official Penn Medicine Team, patients, friends and family are welcome to visit the official registration page online and follow the instructions.

Race for the Cure Schedule:
7:00 AM: Opening Ceremony: 25th Celebration Extravaganza
8:15 AM: 5K Run Start
8:25 AM: 5K Walk / 1-Mile Fun Walk Start

Other ways to show your support.

Can’t make it on Mothers’ Day? You can still support Penn Medicine’s team by making a donation to the team.

If you have questions about joining or would like to tell us why you walk in the Susan G. Komen Race for the Cure, please email Amy Kleger or visit PennMedicine.org/PennRace4Cure