Tobias Sjöblom's projects on molecular changes in colorectal cancer

Multiomics studies of colorectal cancers

The aim of this project is to increase knowledge of colorectal cancer tumorigenesis through detailed characterisation of the genomic, transcriptomic and proteomic landscapes of colorectal tumours and blood samples from Swedish patients. We have previously published a study with whole genome sequencing and transcriptome data for 1,063 tumours where we present cancer-specific genomic and transcriptomic alterations and their associations to clinical characteristics and patient outcome (Nunes at el, Nature, 2024).

We are currently analyzing further aspects of genetics information in this cohort, including constitutional genetics, single-cell transcriptomics, and spatial transcriptomics. The cohort is also included in proteomics studies of blood plasma. The study is possible through collaboration between the U-CAN colorectal cancer investigators at Uppsala University, Umeå University, and KTH.

Discovery and validation of cancer biomarkers in blood plasma and cancer tissue

A good diagnostic plasma biomarker should be specific for the cancer type and be able to accurately identify a patient at an early disease stage. However, most cancer types lack biomarkers for early detection approved for clinical use, and the literature lacks strategies for how biomarker studies should be designed to maximize the chances of success.

We have developed a new study design framework for biomarker discovery based on regulatory authority requirements and novel statistical approaches. Here, we focus on discovery and validation of new diagnostic plasma biomarkers for colorectal, lung, and ovarian cancers by applying the statistical framework to large-scale proteomics and metabolomics data that we have generated from patient samples from the U-CAN cohort. In the next step, we will extend the study to include e.g. breast cancer, prostate cancer and brain tumours.

We are also building a large cohort of home-sampled fingertip blood collected on paper cards that will be subject to biomarker profiling to find candidates for cancer screening tests. The aim is development of sensitive blood tests to detect cancer. We also study biomarkers in cancer tissue, for example a potential biomarker for prediction of response to immunotherapy in malignant melanoma.

Exploiting genetic variation and loss of heterozygosity for novel anti-cancer therapy development

Successful anti-cancer therapies selectively kill cancer cells, while normal tissues are spared. We have developed a concept based on frequent loss-of-function genetic variants that occur naturally in the human population, and cancer-specific loss of heterozygosity (LOH).

As proof of principle for our approach, we have shown that loss-of-function variants of NAT2 make cancer cells sensitive to drugs that are metabolised by this enzyme if they have lost wild-type NAT2 activity through LOH (Rendo et al, Nat Commun., 2020). Normal cells that retain at least one copy of the wild type NAT2 allele are not killed by these drugs as they can still metabolize them.

By similar mechanism, we recently showed how cancer cells deficient in the CYP2D6 enzyme are more sensitive to treatment by two substances, one of which is an already approved cancer medication (Zhang et al, eBioMedicine 2024). We are continuing our studies of loss of NAT2 and CYP2D6 as target for anti-cancer therapy and have initiated studies of further candidate genes for this novel class of therapy with potential application in both adult and pediatric cancers.

We are also studying other novel targets for therapy, including mitochondrial genomic targets and cancer-specific protein isoforms, using cell culture-based approaches.

Evaluation of clinical data parameters for prediction and prognosis in colorectal cancer

We are studying the population of colorectal cancer patients from Uppsala, Dalarna and Gävleborg to evaluate e.g. how tumour and patient characteristics and given treatments affect progression and survival on a population level. The aim is to contribute towards improved predictive and prognostic tools in the clinic.

We primarily base our research on clinical data from national registries, and also have access to molecular data generated in other projects in the research group. We collaborate closely with Professor Bengt Glimelius in this project.