Project Summary - Overall
The mortality rates of breast and pancreatic cancers are intrinsically tied to metastasis. In pancreatic cancer, the
5-year survival rate is only 9% and in ~70% pathological evaluations of the resected tumor, instances of venous
invasion are found. Metastasis is a complex multi-step process involving cancer cells, local vasculature, and the
surrounding microenvironment at multiple sites. Venous invasion in pancreatic cancer, in which cancer cells gain
often invade the portal vein, is an early step in this process and provides the cells a direct path to the liver, the
most common site of pancreatic cancer metastasis. As in pancreatic cancer, invasion past normal breast tissue
barriers is critically tied to breast cancer outcomes. Most breast tumors can be surgically removed, and so
mortality is closely tied to the extent of distant metastasis through lymphovascular invasion. The detection of
lymphovascular invasion in a breast tumor correlates with poor prognosis and is not captured in current molecular
analyses. The spatial organization of cancer cells, and cellular and stromal components of the tumor
microenvironment near and far away from blood vessels is intrinsically three-dimensional, non-symmetric, and
highly heterogeneous. In the TECH units of the Johns Hopkins Center for 3D Multiscale Cancer Imaging, we
will develop a versatile 3D multiscale imaging method, CODA, which will allow us to probe the phenotypic
heterogeneity of tumors from the multi-cm to the micron scale via multiplexing serial imaging. CODA can readily
incorporate other imaging modalities to extract high cellular/molecular content from 3D samples. These include
immunocytochemistry (CODA+IHC), immunofluorescence (CODA+IF), imaging mass cytometry (CODA+IMC)
and spatial transcriptomics/proteomics (CODA+DBiT-seq). These proposed expanded versions of CODA offer
a unique opportunity to produce new 3D multi-omic maps of human PDAC and breast tumors near and far from
blood vessels. CODA and its integrated versions CODA+X will be tested in the RTB units of the Center in both
human/mouse tissue samples and organoids, in breast and pancreatic cancer. Results from these test beds will
provide novel mechanistic insights into venous invasion in breast and pancreatic cancer. Exploiting our extensive
experience in data dissemination, we will make the large datasets and software produced by our CODA+X
platforms and software widely available to the larger cancer research community. The units of the Center will be
co-led by Johns Hopkins/Yale engineers, scientists and physicians. Substantial additional support will be
provided by the Johns Hopkins U., the JH School of Medicine, the Institute for Convergence, the Department of
Pathology, and the Whiting School of Engineering.