Congratulations to Dr Daniel Muñoz-Espín, Early Detection Programme Group Leader, and Dr Jim Korkola, Professor of Biomedical Engineering at OHSU, who have been awarded the CRUK-OHSU Project Award for their project entitled: Dissecting the role of the senescent secretome in tumorigenesis.
Daniel explains the background to the project: Cancer is a disease of aging, and it is hypothesised that this is due to the accumulation of mutations over time. Emerging evidence suggests that generation of a pro-tumour, pro-inflammatory microenvironment plays an important role in promoting the development and outgrowth of early tumours. Senescence is a cell autonomous response to damage and oncogenic stress resulting in a stable cell cycle arrest. It has been determined that senescent cells also accumulate with age in multiple tissues, and building evidence suggests that they may contribute to inflammatory changes and tumourigenesis by secreting a complex cocktail of paracrine factors (the so-called senescence-associated secretory phenotype or SASP). However, the precise SASP factors that perform these pro-tumorigenic functions remain undefined. The difficulty in identifying the responsible SASP factors is that the tumour microenvironment is highly complex, and thus assigning functional impact to any single factor remains a challenge. We have developed microenvironment-microarrays (MEMA), a technology that allows us to screen thousands of unique combinations of matrix proteins and soluble ligands for their impact on cellular phenotypes.
We propose to use MEMA to identify SASP factors that can drive proliferation, differentiation changes, and increased invasiveness in pre-cancerous and early lung and breast cancer cells. Our innovative technology will allow us to:
Aim#1: Define alterations in the early pre-neoplastic microenvironment that could be used to screen for individuals at high risk for the formation of cancerous lesions.
Aim#2: Define factors in the early pre-neoplastic microenvironment that could be targeted for cancer prevention and diagnosis.
Aim#3: Identify factors and related signalling pathways that are important in driving the progression of pre-neoplastic lesions into fully invasive neoplasms, allowing potential targeting of these factors and/or pathways for therapeutic interventions.
SASP factors identified by MEMA will be validated in standard 2-d culture and co-culture systems. We will use proteomics and RNAseq approaches to identify pathways that are activated in early tumour cells in response to SASP factors exposure. Finally, we will employ 3-d bioprinted tissues and mouse xenograft models to study the role of the identified SASP factors in driving tumourigenesis.
These studies will enable us to identify new drivers of early tumorigenesis, provide new markers for detection of early breast and lung lesions, and provide new therapeutic targets for tumour prevention.