Publications by Author: Joanne B Weidhaas

The KRAS-variant is a germline single nucleotide polymorphism (SNP) within the 3'UTR of the KRAS gene predicted to disrupt a complementary binding site (LCS6) for the let-7 microRNA (miRNA). The KRAS-variant is associated with increased risk of various cancers, including lung cancer, ovarian cancer and triple-negative breast cancer, and is associated with altered tumor biology in head and neck cancer, colon cancer and melanoma. To better understand the molecular pathways that may be regulated or affected by the presence of the KRAS-variant allele in cancer cells, we examined its prevalence in the NCI-60 panel of cell lines and sought to identify common features of the cell lines that carry the variant allele. This study provides a step forward towards understanding the molecular and pathological significance of the KRAS-variant.

MicroRNAs have been increasingly implicated in human cancer and interest has grown about the potential to use microRNAs to combat cancer. Lung cancer is the most prevalent form of cancer worldwide and lacks effective therapies. Here we have used both in vitro and in vivo approaches to show that the let-7 microRNA directly represses cancer growth in the lung. We find that let-7 inhibits the growth of multiple human lung cancer cell lines in culture, as well as the growth of lung cancer cell xenografts in immunodeficient mice. Using an established orthotopic mouse lung cancer model, we show that intranasal let-7 administration reduces tumor formation in vivo in the lungs of animals expressing a G12D activating mutation for the K-ras oncogene. These findings provide direct evidence that let-7 acts as a tumor suppressor gene in the lung and indicate that this miRNA may be useful as a novel therapeutic agent in lung cancer.

Lung cancer is the leading cause of cancer deaths worldwide, yet few genetic markers of lung cancer risk useful for screening exist. The let-7 family-of-microRNAs (miRNA) are global genetic regulators important in controlling lung cancer oncogene expression by binding to the 3' untranslated regions of their target mRNAs. The purpose of this study was to identify single nucleotide polymorphisms (SNP) that could modify let-7 binding and to assess the effect of such SNPs on target gene regulation and risk for non-small cell lung cancer (NSCLC). let-7 complementary sites (LCS) were sequenced in the KRAS 3' untranslated region from 74 NSCLC cases to identify mutations and SNPs that correlated with NSCLC. The allele frequency of a previously unidentified SNP at LCS6 was characterized in 2,433 people (representing 46 human populations). The frequency of the variant allele is 18.1% to 20.3% in NSCLC patients and 5.8% in world populations. The association between the SNP and the risk for NSCLC was defined in two independent case-control studies. A case-control study of lung cancer from New Mexico showed a 2.3-fold increased risk (confidence interval, 1.1-4.6; P = 0.02) for NSCLC cancer in patients who smoked <40 pack-years. This association was validated in a second independent case-control study. Functionally, the variant allele results in KRAS overexpression in vitro. The LCS6 variant allele in a KRAS miRANA complementary site is significantly associated with increased risk for NSCLC among moderate smokers and represents a new paradigm for let-7 miRNAs in lung cancer susceptibility.

MicroRNA-155 (miR-155) is an oncogenic microRNA that regulates several pathways involved in cell division and immunoregulation. It is overexpressed in numerous cancers, is often correlated with poor prognosis, and is thus a key target for future therapies. In this work we show that overexpression of miR-155 in lymphoid tissues results in disseminated lymphoma characterized by a clonal, transplantable pre-B-cell population of neoplastic lymphocytes. Withdrawal of miR-155 in mice with established disease results in rapid regression of lymphadenopathy, in part because of apoptosis of the malignant lymphocytes, demonstrating that these tumors are dependent on miR-155 expression. We show that systemic delivery of antisense peptide nucleic acids encapsulated in unique polymer nanoparticles inhibits miR-155 and slows the growth of these "addicted" pre-B-cell tumors in vivo, suggesting a promising therapeutic option for lymphoma/leukemia.

miR-155 is a prominent microRNA (miRNA) that regulates genes involved in immunity and cancer-related pathways. miR-155 is overexpressed in lung cancer, which correlates with poor patient prognosis. It is unclear how miR-155 becomes increased in lung cancers and how this increase contributes to reduced patient survival. Here, we show that hypoxic conditions induce miR-155 expression in lung cancer cells and trigger a corresponding decrease in a validated target, FOXO3A. Furthermore, we find that increased levels of miR-155 radioprotects lung cancer cells, while inhibition of miR-155 radiosensitizes these cells. Moreover, we reveal a therapeutically important link between miR-155 expression, hypoxia, and irradiation by demonstrating that anti-miR-155 molecules also sensitize hypoxic lung cancer cells to irradiation. Our study helps explain how miR-155 becomes elevated in lung cancers, which contain extensive hypoxic microenvironments, and demonstrates that inhibition of miR-155 may have important therapeutic potential as a means to radiosensitize hypoxic lung cancer cells.

Cellular stress responses are potent and dynamic, allowing cells to effectively counteract diverse stresses. These pathways are crucial not only for maintaining normal cellular homeostasis, but also for protecting cells from what would otherwise lead to their demise. A novel class of genes, termed miRNAs, has recently been implicated in the cellular stress response. For example, it has been demonstrated that a cardiac-specific miRNA that is not required for normal development is requisite for a normal cardiac stress response in mice. In addition, we have found that a miRNA family is able to modulate the cellular response to cytotoxic cancer treatment both in vitro and in vivo. In this review, we will discuss these and other important developments in the field. In particular, we will focus on studies that have linked miRNAs to the genotoxic stress response and will suggest how this connection may be both important for our understanding of biology and pertinent for the development of novel cancer therapies.