No abstract

A variety of metastatic cancer cells use actin-rich membrane protrusions, known as invadopodia, for efficient ECM degradation, which involves trafficking of proteases from intracellular compartments to these structures. Here, we demonstrate that in the metastatic breast cancer cell line MDA-MB-231, retromer regulates the matrix invasion activity by recycling matrix metalloprotease, MT1-MMP. We further found that MT2-MMP, another abundantly expressed metalloprotease, is also invadopodia associated. MT1- and MT2-MMP showed a high degree of colocalization but were located on the distinct endosomal domains. Retromer and its associated sorting nexin, SNX27, phenocopied each other in matrix degradation via selectively recycling MT1-MMP but not MT2-MMP. ITC-based studies revealed that both SNX27 and retromer could directly interact with MT1-MMP. Analysis from a publicly available database showed SNX27 to be overexpressed or frequently altered in the patients having invasive breast cancer. In xenograft-based studies, SNX27-depleted cell lines showed prolonged survival of SCID mice, suggesting a possible implication for overexpression of the sorting nexin in tumor samples.

No abstract

Increased breast tissue stiffness is correlated with breast cancer risk and invasive cancer progression. However, its role in promoting bone metastasis, a major cause of mortality, is not yet understood. It is previously identified that the composition and stiffness of alginate‐based hydrogels mimicking normal (1–2 kPa) and cancerous (6–10 kPa) breast tissue govern phenotype of breast cancer cells (including MDA‐MB‐231) in vitro. Here, to understand the causal effect of primary tumor stiffness on metastatic potential, a new breast‐to‐bone in vitro model is described. Together with alginate‐gelatin hydrogels to mimic breast tissue, 3D printed biohybrid poly‐caprolactone (PCL)‐composite scaffolds, decellularized following bone‐ECM deposition through Saos‐2 engraftment, are used to mimic the bone tissue. It is reported that higher hydrogel stiffness results in the increased migration and invasion capacity of MDA‐MB 231 cells. Interestingly, increased expression of osteolytic factors PTHrP and IL‐6 is observed when MDA‐MB‐231 cells pre‐conditioned in stiffer hydrogels (10 kPa, 3% w/v gelatin) colonize the bone/PCL scaffolds. The new breast‐to‐bone in vitro models herein described are designed with relevant tissue microenvironmental factors and could emerge as future non‐animal technological platforms for monitoring metastatic processes and therapeutic efficacy.

We aim to quantify and categorize point-of-care ultrasound (POCUS) usage by pediatric practitioners and trainees at our tertiary care center, and assess the degree of interest from pediatric residents, fellows, and program leaders for integrating POCUS into their training. Data was collected via online survey, evaluating the current use of POCUS in clinical decision making, desire for further formal training, and opinions on the importance of POCUS to future clinical practice. In total, 14 program directors/assistant program directors (PD/APDs) representing 10 of 15 training programs, 30 of 95 fellows representing 9 of 15 fellowships, and 32 of 82 residents responded. From PD/APDs, only 2 of the programs reported active use POCUS for clinical decision making, but 13 of the fellows and 9 residents reported doing so. In regard to desire for a formal POCUS program, 30.8% of PD/APDs, 43.8% of fellows without current curricula, and 87.5% of residents were interested in participating in such a program. When considering specialty, some non-acute care-based PD/APDs and fellows at our institution felt that POCUS was important to future practice. Pediatric subspecialty PD/APDs and their fellows had divergent outlooks on the importance of POCUS in future practice. Finally, an overwhelming majority of residents at our institution expressed a desire to learn, and half believing it will be important to future practice. Based on the degree of interest, medicolegal considerations, and trajectory of patient care, pediatric residency and fellowship programs should strongly consider integrating POCUS education into their curricula.