Extracellular Matrix

Molecular Imaging of the Extracellular Matrix and its Avenues for Metastasis (P50CA103175)

We will develop and clinically test endomicroscopic Collagen I (Col1) fiber imaging with an innovative ultra-compact fiber-optic biopsy needle-compatible endomicroscope that is optimized for second harmonic generation (SHG) microscopic detection of Col1 fibers. We will integrate this endomicroscope with a routinely used clinical 14-gauge biopsy needle for SHG Col1 imaging in preclinical and clinical studies. Col1 fibers will be detected in primary breast tumors at the time of biopsy to predict lymph node involvement in breast cancer patients. The assessment of lymph node involvement, which is the most important predictor of prognosis, early on in the clinical management of breast cancer patients, would be of significant advantage in selecting treatment options at the early time of the initial breast biopsy. Col1 fibers are an important component of the extracellular matrix (ECM) in breast tumors, and increased stromal Col1 fibers facilitate breast tumor formation, invasion, and metastasis. High Col1 fiber density in primary tumors promotes metastasis as cancer cells migrate along dense Col1 fiber avenues within metastatic primary tumors to form metastatic nodules. We will therefore evaluate Col1 fiber density as an imaging biomarker to predict tumor aggressiveness and lymph node metastasis. Col1 fibers will be detected by optical SHG microscopy, a highly sensitive and noninvasive technique for imaging intrinsic signal from Col1 fibers. We observed an increased Col1 fiber density in lymph node positive (LN+) compared to lymph node negative (LN-) patients using ex vivo primary tumor specimens from breast cancer patients. Molecular optical endomicroscopic SHG imaging of Col1 fibers, which directly reveals ECM integrity and structure, may serve as a surrogate marker to predict metastasis. We will test this hypothesis in three Aims. In Aim 1, we will quantitatively characterize SHG-detected Col1 fiber signatures in primary tumor specimens from breast cancer patients and evaluate if the quantitative Col1 fiber parameters ‘fiber distance’ and ‘fiber volume’ predict lymph node status. In Aim 2, we will develop, test, and optimize an ultra-compact fiber-optic SHG endomicroscope to detect Col1 fibers. In Aim 3, we will perform the first clinical feasibility study with this fiber-optic SHG endomicroscope during standard ultrasound-guided breast biopsy procedures and thereby obtain SHG Col1 images that can help predict lymph node metastasis. In Aims 1 and 3, we will also correlate Col1 fiber density with standard breast cancer prognostic markers to determine the ability of Col1 fiber density to uniquely select a population of patients that are at risk for lymph node involvement and potentially systemic disease. On a wider perspective, the device being built will also be useful for future applications such as detecting response to stromal depletion therapies that improve drug delivery in desmoplasmic tumors, and predicting drug delivery. This project is in collaboration with Dr. Xingde Li.