Stromal mediated DNA damage promotes high grade serous ovarian cancer initiation.

The fundamental steps in high-grade serous ovarian cancer (HGSOC) initiation are unclear, thus providing critical barriers to the development of prevention or early detection strategies for this deadly disease. Increasing evidence demonstrates most HGSOC starts in the fallopian tube epithelium (FTE). Current models propose HGSOC initiates when FTE cells acquire increasing numbers of mutations allowing cells to evolve into serous tubal intraepithelial carcinoma (STIC) precursors and then to full blown cancer. Here we report that epigenetically altered mesenchymal stem cells (termed high risk MSC-hrMSCs) can be detected prior to the formation of ovarian cancer precursor lesions. These hrMSCs drive DNA damage in the form of DNA double strand breaks in FTE cells while also promoting the survival of FTE cells in the face of DNA damage. Indicating the hrMSC may actually drive cancer initiation, we find hrMSCs induce full malignant transformation of otherwise healthy, primary FTE resulting in metastatic cancer in vivo . Further supporting a role for hrMSCs in cancer initiation in humans, we demonstrate that hrMSCs are highly enriched in BRCA1/2 mutation carriers and increase with age. Combined these findings indicate that hrMSCs may incite ovarian cancer initiation. These findings have important implications for ovarian cancer detection and prevention.

Stromal-Modulated Epithelial-to-Mesenchymal Transition in Cancer Cells.

The ability of cancer cells to detach from the primary site and metastasize is the main cause of cancer- related death among all cancer types. Epithelial-to-mesenchymal transition (EMT) is the first event of the metastatic cascade, resulting in the loss of cell-cell adhesion and the acquisition of motile and stem-like phenotypes. A critical modulator of EMT in cancer cells is the stromal tumor microenvironment (TME), which can promote the acquisition of a mesenchymal phenotype through direct interaction with cancer cells or changes to the broader microenvironment. In this review, we will explore the role of stromal cells in modulating cancer cell EMT, with particular emphasis on the function of mesenchymal stromal/stem cells (MSCs) through the activation of EMT-inducing pathways, extra cellular matrix (ECM) remodeling, immune cell alteration, and metabolic rewiring.

Distinct Chronic Post-Viral Lung Diseases upon Infection with Influenza or Parainfluenza Viruses Differentially Impact Superinfection Outcome.

Chronic obstructive pulmonary disease (COPD) and asthma remain prevalent human lung diseases. Variability in epithelial and inflammatory components that results in pathologic heterogeneity complicates the development of treatments for these diseases. Early childhood infection with parainfluenza virus or respiratory syncytial virus is strongly associated with the development of asthma and COPD later in life, and exacerbations of these diseases correlate with the presence of viral RNA in the lung. Well-characterized animal models of postviral chronic lung diseases are necessary to study the underlying mechanisms of viral-related COPD and asthma and to develop appropriate therapies. In this study, we cross-analyzed chronic lung disease caused by infection with Sendai virus (SeV) or influenza A virus in mice. Differences were observed in lesion composition and inflammatory profiles between SeV- and influenza A virus-induced long-term lung disease. In addition, a primary SeV infection led to worsened pathologic findings on secondary heterologous viral challenge, whereas the reversed infection scheme protected against disease in response to a secondary viral challenge >1 month after the primary infection. These data demonstrate the differential effect of primary viral infections in the susceptibility to disease exacerbation in response to a different secondary viral infection and highlight the usefulness of these viral models as tools to understand the underlying mechanisms that mediate distinct chronic postviral lung diseases.