Disease progression and recurrence are major barriers to surviving breast cancer. Understanding the etiology of recurrent or metastatic breast cancer and underlying mechanisms is critical for the development of new treatments and improved survival. Here, we report that two commonly over-expressed breast cancer oncogenes, Ron and DEK, cooperate to promote advanced disease through multi-pronged effects on β-catenin signaling. The Ron receptor is commonly activated in breast cancers, and Ron over-expression in human disease stimulates β-catenin nuclear translocation and is an independent predictor of metastatic dissemination. Dek is a chromatin-associated oncogene whose expression has been linked to cancer through multiple mechanisms, including β-catenin activity. We demonstrate here that Dek is a downstream target of Ron receptor activation in murine and human models. The absence of Dek in the MMTV-Ron mouse model led to a significant delay in tumor development, characterized by decreased cell proliferation, diminished metastasis, and fewer cells expressing cancer stem cell markers. Dek complementation of cell lines established from this model was sufficient to promote cellular growth and invasion in vitro and in vivo. Mechanistically, Dek expression stimulated the production and secretion of Wnt ligands to sustain an autocrine/paracrine canonical β-catenin signaling loop. Finally, we show that Dek over-expression promotes tumorigenic phenotypes in immortalized human mammary epithelial MCF10A cells and, in the context of Ron receptor activation, correlates with disease recurrence and metastasis in patients. Overall, our studies demonstrate that DEK over-expression, due in part to Ron receptor activation, drives breast cancer progression through the induction of Wnt/β-catenin signaling.

One of the major concerns in the application of nanocarriers in oncology is their scarce penetration capacity in tumoral tissues. Living organisms (cells and bacteria) present the capacity to navigate autonomously following chemical gradients being able to penetrate deeply into dense tissues. Currently, the possibility to employ these organisms for the transportation of therapeutic agents or nanocarriers has received huge attention. Herein, a new approach to deliver drug‐loaded nanoparticles achieving high penetration in tumoral matrices is presented. Escherichia coli bacteria wall is decorated with azide groups, whereas alkyne‐strained groups are incorporated on the surface of mesoporous silica nanoparticles loaded with a potent cytotoxic compound, doxorubicin. Both functional groups form stable triazole bonds by click‐type reaction allowing the covalent grafting of nanoparticles on living bacteria. Both motility and penetration capacity are evaluated in a 3D tumoral matrix model composed by a dense collagen extracellular matrix containing human fibrosarcome cells. The results confirm that bacteria are able to transport the nanoparticles crossing a thick collagen layer being able to destroy almost 80% of the tumoral cells located underneath. These findings envision a powerful strategy in cancer treatment by allowing a homogeneous distribution of therapeutic agents in the malignancy.

The potential impact on patient outcome of different Minimal residual disease (MRD) levels at time of transplant in patients with lymphoblastic leukemia undergoing allogeneic hematopoietic SCT (HSCT) remains uncertain. In this study, we quantified MRD levels at time of transplant using multiparameter flow cytometry (MFC). Mononuclear cells from marrow aspirates were obtained from 102 adult and child patients before their conditioning regimen. Quantification of MRD levels was carried out by detecting patient-specific leukemia-associated immunophenotypes using four-color MFC. Thirty patients exhibited measurable levels of MRD at the time of transplant, with low levels (0.01 to p0.1%) in 12 cases, intermediate levels (40.1 to p1%) in 8 cases and high levels (41%) in 10 cases. The leukemia-free survival (LFS) rates were 65.9±7.0%, 42.9±15.7% and 0% for negative, low levels p0.1% and intermediate-high levels 40.1%, respectively (Po0.001, log-rank test). Overall survival (OS) was 52.3 ± 7.6%, 28.6 ± 13.8% and 0% for MRD-negative, low levels p0.1% and intermediate-high levels 40.1%, respectively (Po0.001, log-rank test). Multivariate Cox analysis confirmed that detection of leukemia cells by flow cytometry at transplant was the most significantly adverse factor for OS, LFS and EFS after transplant.