Biophysical Roles of Pre-Metastatic Niche Evolution on Transport of Circulating Tumor Cells

Exploring the earliest events that promote circulating tumor cells (CTCs) to arrest on vessel wall at future metastatic sites will expose new targets for rational prevention. In addition to biological factors, the physical transport of CTCs and interactions with the microenvironment are regarded as key determinants of the metastatic potential. Recent studies suggest that distant microenvironments are primed and ready to entrap CTCs, creating a pre-metastatic niche for initiating metastasis. Our goal is to determine biophysical modulation of CTC transport by the pre-metastatic niche initiated by PLTs using orthotropic mouse tumor models, novel microfluidics in collaboration with Dr. Lidong Qin and multiscale/multi-physics computational transport models in collaboration with Dr. Milos Kojic. Significance of this study will establish a scientific framework for understanding roles of the pre-metastatic niche in physical oncology for rational prevention of metastasis. This project is being supported by U01 grant which is the part of the Physical Sciences-Oncology Network (PS-ON) of the National Cancer Institute (NCI). View our research project in the Physical Science-Oncology Network, NCI

The image shows immunofluorescence imaging of the lungs in mice-bearing primary breast cancer. Increased accumulation of platelets (red) and fibrinogen (green) was found (nuclei in blue).

Spatio-Temporal Heterogeneity in Tumor Microenvironments as a Novel Driver of Resistance to Systemic Anti-Cancer Therapeutics

Heterogeneous responses of metastatic tumors growing in the different organs to anticancer therapeutics have long been recognized in the clinic. However, little is known about the exact mechanisms for the organ-specific heterogeneity. We have reported that cross-talk between cancer cells and the organ microenvironment, the development and function of tumor-associated blood vessels and dense stroma formation in tumors could create complexed tumor heterogeneities. These heterogeneities can hinder drug delivery and insufficient drug delivery to tumors below the threshold drug concentration that can induce cytotoxic effects on cancer cells generates “drug delivery-based therapeutic resistance in vivo” even for drugs with proven efficacy against cancer cell lines in vitro. This research project has been supported by The Center for Immunotherapeutic Transport Oncophysics (CITO) which is also part of PS-ON of the NCI.

The image shows heterogeneous distribution of intravenously injected liposomal doxorubicin (red) among primary breast cancer cells (green) in mice.

Establishment of Novel Isogenic Pairs of Wild Type and Mutant Induced Pluripotent Stem Cell Lines from SATB2 Associated Syndrome Patient for Analysis of Genotype-Phenotype Correlation

The SATB2-associated syndrome (SAS) is recently described as a very rare pediatric disease characterized by severe developmental delay / intellectual disability with absent or limited speech development, behavioral problems, seizures, autistic spectrum disorder, craniofacial abnormalities, dysmorphic features, skeletal anomalies, osteopenia, and/or feeding difficulties.  So far, less than 200 cases of genetic variants in SATB2 gene have been reported. The SATB2 gene encodes a protein of 733 amino acids with two CUT domains and a homeodomain. The variants of point mutations were often shared by multiple individuals with common alterations in CUT domain, suggesting hotspots. Recently, novel miss sense mutation in CUT domain was reported in a patient who has unique clinical phenotypes including breathing abnormalities and involuntary hand movements. The goal of our new research is to collect data to reveal the consequences of the novel mutation using induced pluripotent stem cell lines (iPSC) from patient’s peripheral blood and its isogenic control cells utilizing CRISPR-Cas9 system to correlate genotype and phenotype. our next goal is to develop mouse model which carries same point mutation to study phenotype-genotype correlation in vivo and develop potential gene therapy using nanocarriers. Image shows our computational modeling for 3D structure of SATB2 Cut domain with the point mutation interacted with DNA