For Sadik Esener, Ph.D., fighting cancer is personal.
Before joining Oregon Health & Science University, Esener served for 30 years on faculty at the University of California, San Diego. With a background in electrical engineering and nanoengineering, he was focused on cancer nanotechnology. Tragically, within the span of a month, Esener lost both his wife and mother to cancer.
"I was deeply frustrated because they both passed away from cancer while I was working at one of the best cancer centers," he said. "I decided to change my course."
That loss shifted his focus toward early detection, which he saw as essential for saving lives.
Esener has led the OHSU Knight Cancer Institute's Cancer Early Detection Advanced Research Center, known as CEDAR, since the center's inception, and holds the Wendt Family Endowed Chair in Early Cancer Detection, Biomedical Engineering in the OHSU School of Medicine.
Founded in 2017 as part of the $1 billion Knight Cancer Challenge initiated by Phil Knight, co-founder of Nike, and his wife, Penny, CEDAR was one of the first centers dedicated to detecting and preventing lethal cancers at their earliest stages.
Esener was drawn to its mission and the opportunity to create a world-class, multidisciplinary center. Today the center brings together more than 200 researchers — from mathematicians and computer scientists to biologists, physicians and engineers — to advance cancer detection and treatment.
"At CEDAR, everyone has an equal voice," Esener said. "Some of the most brilliant ideas come from trainees. I believe everyone's ideas should be listened to carefully."
A key asset at CEDAR is its use of advanced imaging technology, essential for breakthroughs in understanding cancer's origins and progression. CEDAR researchers are working to uncover how cancer begins, develops and potentially metastasizes.
"There are many cancers that don't metastasize or become invasive," Esener said. "And some conditions, called pre-malignant, may increase a person's cancer risk without turning into cancer. Imaging helps us determine which of these may become invasive."
At CEDAR, researchers employ multiple imaging levels. Magnetic Resonance Imaging, or MRI, commonly used in clinical settings, detects cancers that are often already advanced. Immunohistochemistry is used to observe how immune cells interact with tumors. Another technique, spatial multi-omics imaging, reveals the detailed interactions between cells within the tumor, almost as if to translate how the cells are "talking" to one another.
"With imaging, we observe tumor cells 'convincing' surrounding healthy cells to help them grow," Esener explained. "Instead of killing the healthy cells, tumor cells engage with them, transforming them."
CEDAR uses electron microscopy to observe interactions at the nano level, revealing how a cancer cell changes a normal cell. Understanding these interactions may help researchers develop early detection systems and interventions.
Here are just a few of the CEDAR researchers using imaging to advance the frontiers of cancer detection and prevention:
Jessica Riesterer, Ph.D.
Riesterer is a staff scientist with CEDAR. Previously, she worked in the lab of Joe Gray, Ph.D., now professor emeritus, on metastasized cancer, but for the past two years has transitioned to early cancer detection.
She uses electron microscopes at OHSU's Multispatial Microscopy Core to conduct research. Riesterer is an expert on scanning electron microscopy, a technique that uses a focused beam of electrons to examine the surface of a material and produce high-resolution images. The electrons interact with the sample's atoms, generating signals that are collected and combined to form an image. This method can reveal information about a sample's surface topography, composition and three-dimensional structure.
"At CEDAR, we're looking for the earliest changes, from when a cell is normal to pre-malignant or malignant," Riesterer said. "And we can look inside the cells and compare normal versus diseased and find the exact moment the cell starts to look different."
Being able to pinpoint the exact moment a cell changes and becomes cancerous is a key to developing early interventions. Riesterer also uses volume electron microscopy, where scientists can take high-resolution images of cells in three dimensions.
"You can look at an entire tissue at 4 nanometers per pixel, which is roughly like cutting a single strand of hair into a thousand pieces," she said.
As a staff scientist, Riesterer assists other researchers with their projects as well as working on her own research. One of her current projects is finding a way to streamline the data sets to make health discoveries faster.
"We can get an image stack of human tissue or mouse tissue and then reconstruct that and make three-dimensional models of what the sample looked like," she said. "The data sets are huge. Each map that I take is between 600 and 1,000 images. And then if you're doing it on multiple patients or multiple animals, it takes a long time. So that's why we're working on this computational pipeline to speed the process up so the patient can get results faster."
Beyond basic science discoveries and faster processes, Riesterer said her research and that of other CEDAR scientists is to use high-resolution imaging technology to find individual pathways for cancer treatment by seeing at an individual level how, when and why cells change.
"We want to get to the point of personalized medicine, so if we can take samples from each person, from their disease, and look at it as it's progressing, we can start to get some clues on how to treat it specifically," she said.
"I like to think of it as every person is their own chemistry experiment," she continued. "Two people who come into the clinic and they have the same breast cancer, same subtype — they still experience a whole different world of environmental factors and/or hereditary factors. To give these people the same drug, it may work for one, but not the other. Just because we're all made up just a little differently."
Young Hwan Chang, Ph.D.
Chang, an associate professor of computational biology and biomedical engineering in the OHSU School of Medicine, is an engineer by training. He came to OHSU in 2015 to work in the OHSU Center for Spatial Systems Biomedicine, or OCCSB, under the leadership of Gray, the professor emeritus. OCCSB scientists take a systems biology approach, meaning they are looking at spatial scales at the tiniest molecular level through the whole person, over time, to observe changes.
In Chang's lab, his team is developing a new computational tool to help understand where cancer cells are located and how they interact with each other using multiplex tissue imaging. To do this, they use the latest machine-learning and deep-learning methods to analyze data in depth and integrate information from different sources.
Traditional methods for studying tissue samples involve basic staining techniques, known as hematoxylin and eosin staining, which help identify different types of cells but offer limited insights into their behavior. Instead, Chang's lab uses a technique called multiplex tissue imaging to identify different cell types and states, like whether an immune cell is active or exhausted, and see how these states influence interaction with cancer cells.
"You can characterize individual cells in detail," he said. "With an immune cell, you can see if this cell is exhaustive or active. If it's active and near a cancer cell, it may be able to kill a cancer cell. This approach allows us to understand how immune cells interact with cancer cells based on their proximity and state."
As part of his work at CEDAR, Chang is developing a foundational model for multiplexed tissue imaging. Chang said multiplex imaging faces technical challenges, including the number of markers it can handle. In a recent paper in Communications Biology, his team introduced a new deep-learning method that reduces the required markers from 25 to nine.
"This approach makes the process faster, allows for more detailed analysis and lowers costs," Chang said. "We've shown that our predictions are reliable and applicable to different types of cancer, like breast and colorectal cancer, proving that it works well with various tissues."
Xiaolin Nan, Ph.D.
A physical chemist by training, Nan, an associate professor of biomedical engineering in the OHSU School of Medicine and member of CEDAR, worked on coherent Raman scattering microscopy while earning his Ph.D. and super resolution microscopy as a postdoc, both leading-edge technologies at the time. Coherent Raman scattering is a method that uses two very fast lasers to take pictures of samples without needing any special stains, while also being able to tell different chemicals apart. Super-resolution microscopy, on the other hand, is a technique that breaks the usual limits of how clearly small details are visible with a regular microscope, showing tiny features as small as a few nanometers.
Now in his lab and at CEDAR, Nan's research tackles cancer by revealing how biological molecules work together at scales from single molecules — nanometers — to multicellular structures — millimeters. He is developing advanced imaging techniques that achieve imaging of multiple species and across multiple length scales. His team developed imaging tools such as multispectral super resolution microscopy, which they call MSSRM, to facilitate multicolor imaging with minimal crosstalk between the color channels; improved DNA-mediated points accumulation for imaging nanoscale topography, or DNA-PAINT, for much larger field-of-view and faster imaging speed; and, optimized correlative light and electron microscopy, known as CLEM, to combine super-resolution microscopy with the top-notch electron microscopes installed at OHSU.
"Among the most exciting aspects of our work is to use these tools to understand the molecular and cellular changes in early cancer," Nan said.
"Changes in the tissue ultrastructure at early stages of cancer may evade conventional imaging, but they could be readily captured on our microscopes," he continued. "This could help us better understand cancer development and, hopefully, lead to discovery of new biomarkers."
Nan is studying how certain molecules, like Ras proteins and HER receptors, function in cells to better understand the complex networks that control cell behavior. For instance, in pancreatic cancer, Nan said more than 90% of tumors have what is known as the K-RAS mutation. To treat pancreatic cancer, it's important to understand how this mutated K-RAS behaves differently from the normal version. In other types of cancer, researchers focus more on HER receptors and how they work together to drive cancer and make it harder to treat.
Nan and team build tools to detect single molecules. His lab is also working on early cancer detection at CEDAR, aiming to create super-sensitive tests to spot cancer-related markers in blood or tissue samples. Their recent research, published in ACS Nano, shows how they use a method called surface plasmon resonance to detect these molecules.
Sebnem Ece Eksi, Ph.D.
Eksi, an assistant professor of oncological sciences in the OHSU School of Medicine and CEDAR, is at the forefront of a new area of cancer research: the communication between the nervous system and cancer, also known as cancer neuroscience. In a 2021 study published in Nature Communications, Eksi's team discovered two signaling proteins used by nerve cells that become active in prostate tumors and are associated with increased tumor aggressiveness. Eksi said these types of discoveries would not be possible without advanced imaging technology.
"It has been observed since 1897 that the nervous system and chronic stress are linked to cancer growth," Eksi said. "Only recently, with advanced imaging tools, have we been able to observe these interactions directly and begun to understand how nervous system signaling may influence cancer cell behavior. Emerging evidence suggests that signaling from the nervous system could play a role in promoting more aggressive cancer phenotypes."
Since the publication of that study, Eksi and her team have focused on using spatial imaging to develop specific markers that stimulate cancer cells. They use multiplex imaging to simultaneously detect multiple disease-specific biomarkers in a tissue sample.
Looking specifically at prostate tumors, Eksi seeks to discover why some cancers become more aggressive and spread, while others do not. One pathway of interest is the role of the nervous system, particularly certain nerves that activate a "fight or flight" response, potentially driving cancer cells to spread and proliferate.
Using spatial imaging, the researchers can home in on what the synaptic molecules are doing in a prostate tumor.
"What we've learned in the past few decades is when we detect these cancers at late stages, treatment options are limited and it takes a toll on patients because of how invasive treatments are at that point," Eksi said. "That's why the work of CEDAR is so important. Treatment options at early stages of tumor growth can be targeted."
