Pilot: Point-of-care Functional Microscope to Reveal the Role of Metabolic Reprogramming in Breast Cancer Radiation Resistance Development

ABSTRACT: Tumor cell metabolism is highly dynamic and strongly influenced by its local vascular microenvironment, gaining a systems-level view of tumor metabolism and vasculature in vivo is essential in understanding many critical problems in cancer biology and therapeutics. Many types of human tumors can flexibly switch between glycolysis and mitochondrial metabolism under a range of oxygen conditions, which renders some therapies ineffective, therefore capturing both metabolism and vascular microenvironment alterations will be critical in understanding tumor treatment resistance and recurrence mechanisms. Several tools with a variety of practical and scientific limitations are currently used to report on different endpoints to piece together a narrative on tumor metabolism or vasculature. Unfortunately, none of them can simultaneously quantify the major metabolic and vascular parameters in vivo in real-time at cellular level resolution, though it is vital to do so for both basic biology science and therapeutics studies. Furthermore, most of them are: (1) housed in core facilities that require transporting samples or animals to their site; (2) costly in equipment and user fees (often hundreds dollars /service), and (3) time-consuming (few days) due to special sample preparation and complicated data processing. These factors all limit their access for high frequency measurements in cancer research. To maximize the ease and accessibility in obtaining in vivo tumor metabolism and vasculature measurements, it is highly significant to develop multi-modal metabolic tools with point-of-care and low-cost footprints, allowing one to quantify tumor metabolic and vascular endpoints together in vivo in real-time with easy access, in the aim of advancing many critical cancer biology inquires. In this pilot project, we aim to develop a point-of-care and easy-to-use functional microscope capable of simultaneously imaging the several major metabolic and vascular parameters of small tumors in vivo at cellular level resolution (Aim 1). To demonstrate the proof-of-concept of our technique, we will utilize our microscope to reveal the role of radiation induced HIFs and the following metabolic and vascular changes in radio-resistance (RR) development in breast cancers (Aim 2). Our novel techniques will significantly impact cancer research by providing a point-of-care approach for quantifying tissue metabolism and vasculature together in vivo in near real-time at low-cost and will have broad impact across many biomedical fields through the lens of tissue bioenergetics and vasculature.