Summary
More than 90% of all cancer-related deaths are caused by metastasis, the spread of cancer from its origin.
By the time most cancer metastases become clinically visible, the disease has progressed too far to benefit from
early-stage interventions such as surgery or radiation. Thus, new approaches accessing specific diagnostic
biomarkers are highly desired to improve therapeutic outcomes. Microenvironmental signatures such as
extracellular matrix (ECM) alterations, stromal composition, or immune components exhibit critical determinants
of metastatic dissemination broadly across cancers. Herein, the main goal of this proposal is to converge the
disease hall markers and rational design of biomolecular engineering to develop multidisciplinary approaches
towards precision diagnostics of cancer metastasis. As metastases start to invade, they alter the extracellular
matrix through aberrant proteolytic activities that could be leveraged as biomarkers. The applicant set out to
systematically identify proteases expressed in metastatic colorectal cancer (CRC) by transcriptomic and
proteomic analysis. To improve the detection sensitivity, it is proposed to integrate the proteolytic activity to
formulate a library of enzyme activated sensors by reengineering the ECM targeting nanobody with
extraordinarily tumor targeting efficacy for maximal on-target signal generation (Aim 1). To optimize the detection
specificity, the multiplexity of these activity-based sensors will be extensively expanded for disease classification
using CRISPR-Cas-based nucleic acid barcode readout. Preliminary investigation into the in vivo DNA barcodes
revealed that they could be detected noninvasively as a urinary reporter, but could also enable portable detection
on paper (Aim 2). Beyond initial diagnosis, disease stratification and treatment monitoring are critical to
establishing a robust therapy. The novel sensors will thus be evaluated for noninvasive tumor monitoring and
imaging in disease recapitulating metastatic CRC models (Aim 3). Successful completion of these three aims
would offer a tumoral activation responsive, genetically encoded tracking (TARGET) platform can 1) unveil new
biology at the metastasis-specific tumor microenvironment, 2) provide a completely noninvasive way to track
tumor metastasis, and 3) offer a pipeline for validating novel therapies, which are currently unachievable by
single modality agents. This project requires innovative integration across several fields. The candidate has
assembled an exceptional team to help her achieve the goals of technology development and career transition,
including her mentor Dr. Sangeeta Bhatia (MIT, medical engineering) and Drs. Tyler Jacks (MIT, tumor genetics),
Dr. Richard Hynes (MIT, extracellular matrix), Dr. Frank Gertler (MIT, cell motility) and Dr. Shawn Chen (NIH,
theranostics) on the mentoring committee. This training period will allow the candidate to gain experience in
tumor microenvironment network, pre-clinical cancer models and analytical chemistry. In the future, the principles
of this modular platform could apply to other disease areas. The research program here aligns well with the
candidate’s long-term goal to develop multi-scale engineered tools in the context of cancer.