PROJECT SUMMARY
Increased glucose and fat metabolism are essential for tumor progression. Recent work showed that cold-
induced activation of brown adipose tissue (BAT), a unique adipose tissue which produces heat via glycolysis
and fat metabolism, suppressed tumor progression in several cancer mouse models due to competition for
glucose and fat resources. White adipose tissue (WAT) is an endocrine tissue that functions as the main energy
storage organ in our body, storing lipids and secreting hormones that regulate various biological functions,
including appetite, glucose and fat metabolism, and insulin hemostasis. It is commonly used in clinical
procedures such as liposuction and fat transplantation in plastic surgery. Thus, WAT could be readily
used for cellular therapy. Here, we propose to showcase the utility of this approach, which we term as Adipose
Manipulation Transplantation (AMT), for cancer therapy. We plan to bioengineer WAT and adipose organoids
to become more BAT-like, which will increase their glucose and fat utilization, along with having increased
glucose uptake and fat storage. This will be done using CRISPR activation (CRISPRa) to upregulated genes
that are involved in BAT function and glucose and fat metabolism. Our preliminary results already show that co-
culturing CRISPRa engineered BAT-like adipocytes with five different cancer cell lines suppresses their
growth. Furthermore, implanting engineered adipose organoids with xenografts or in two cancer genetic
mouse models (breast and pancreas) significantly reduces cancer growth. Finally, engineering
adipocytes from eight different human breast cancer patients surgically resected tissue and co-culturing
them with cancer organoids significantly reduced organoid growth. Here, we plan to build on these results.
We will engineer adipocytes and organoids to have increased glucose and fat utilization by upregulating
combinations of genes not only involved in browning, but also in glucose and fat metabolism and glucose
transport and test their ability to reduce cancer growth in various cancer cell models (Aim 1). We will also test
the ability of these CRISPRa gene combinations in adipose organoids to suppress cancer in xenograft cancer
models from various cell lines (breast, colon, pancreas, prostate) and in several genetic mouse models (breast
and pancreas) (Aim 2). Finally, to further dissect the translational potential of this approach, we will use surgically
resected tumor tissue from breast cancer patients, isolate and engineer their adipocytes and then co-culture
them with their respective tumor to assess their therapeutic potential (Aim 3). This will be done across the full
spectrum of human breast cancer stages, including different stages of breast cancer (adjuvant, late recurrence,
metastasis, challenging-to-treat breast cancer subtypes and BRCA mutations). Combined, this project will
develop a novel ‘CAR T like’ therapeutic approach to treat cancer utilizing bioengineered adipocytes, having
tremendous therapeutic implications for cancer treatment.