Collective Cell Migration

Collective cell migration is a fundamental multicellular activity that plays essential roles in numerous physiological and pathological processes.  The fascinating capability of cells to organize into functional structures that are much bigger than themselves is a central question in developmental biology and regenerative medicine.  Emerging evidence has also revealed that the invasion and metastasis of malignant tumors utilize the same cooperative mechanisms.  Nevertheless, little is known about how cells communicate among themselves during the dynamic migratory processes and how cells collectively utilize cues in the microenvironment, including global geometric guidance, local cell-cell interactions, and other physicochemical factors, for the emergence of the structural hierarchy across multiple length scales.  Our team has identified novel mechanoregulation schemes enabling local cell-cell organization and global tissue level coordination of cell movement in an autonomous manner.  We envision a new paradigm in collective cell migration by developing a systems mechanoregulation framework integrating dynamic single cell analysis, biomanufacturing of 3D microenvironments, biomechanical analysis, and computational systems biology to decipher the multicellular mechanisms governing collective cell migration under diverse physiological conditions.   

Tumor Heterogeneity and Cooperation

Heterogeneity is a hallmark of cancer.  In particular, cancer cells with innate plasticity and diverse phenotypes are hierarchically and functionally coordinated and interacted with the tumor microenvironment.  The evolving cancer subpopulations collectively contribute to the most devastating aspects of cancer, including dormancy and relapse, multidrug resistance, and metastatic colonization.  In the postgenomic era, new technologies, such as single cell transcriptomics, high-throughput epigenomic analysis, and super-resolution imaging, are being developed to identify key molecular mechanisms that regulate cancer progression.  Nevertheless, current approaches for characterizing tumor heterogeneity often require physical isolation or invasive manipulation of cells to identify genotypic signatures and phenotypic functions. The hierarchical organization, cell-cell coordination and cancer niche are inherently lost in the standard practice.  More importantly, the dynamic response of the cancer subpopulations under external perturbations cannot be studied.  The abilities to identify cancer subpopulations in native tumor microenvironments and monitor their dynamic responses to external stimuli will challenge our current understanding of tumor progression.

Clinical Diagnostics

Rapid detection of pathogenic agents is critical towards judicious management of infectious diseases, such as urinary tract infection and sepsis, especially in emergency situations and high-risk areas such as hospitals, airports, rural clinics, and temporary clinics established in response to disasters.  In settings where highly infectious pathogens are suspected, point-of-care detection will lead to timely initiation of appropriate treatments, which will reduce the infected individuals’ morbidity and mortality, as well as address public health concerns by efficient triaging of the uninfected from the infected.  Within this context, we design and implement microfluidic, point-of-care diagnostic systems to address the unmet critical need for rapid identification and quantification of microbes.  Specific projects include:

• Pathogen identification for urinary tract infection, VAI, and sepsis diagnosis 
• Single cell antimicrobial susceptibility testing
• Dysbiosis monitoring

Dynamic Multigene Analysis of Single Cells

The systematic investigation of complex biological systems requires novel biosensors for rapid quantification of biological events.  We have established several innovative molecular schemes for detecting key signaling events (e.g., mRNA, miRNA, protein, and transcription factors) by combining specific recognitions achieved by innovative molecular designs and FRET/quenching transduction mechanisms.  The molecular biosensors are capable of measuring the real-time dynamics of cellular events quantitatively.   Using these nanoengineered biosensors, we have demonstrated specific detection of single nucleotide mismatch, real-time monitoring of intracellular mRNA hybridization, strain-specific detection of pathogen 16S rRNA, and separation-free detection of transcription factors.