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Parallel Speakers

Cancer initiation and growth

Kristian Pietras, Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University Cancer Centre, Lund University, Lund, Sweden
E-mail: Kristian.Pietras@med.lu.se

Exploring the organizational principles of the tumor microenvironment to reveal functional heterogeneity
Recent efforts analyzing tumor composition at single-cell resolution suggest a more intricate
cellular complexity than previously recognized, indicating the need to study the context of the
malignant microenvironment with improved detail. Conceivably, cellular microniches form
functional units influenced by the origin and context of each constituent cell type. Our
overarching aim is to functionally define the cellular elements of a tumor through an innovative
set of integrated basic, pre-clinical and translational studies. Through the use of spatially
resolved high-content technologies, we are mapping cellular interplays in microniches in order
to define organizational principles of the tumor microenvironment. Ultimately, we are aiming to
couple functional properties to tissue architecture. As a case-in-point we have detailed
signaling pathways involving specific cancer-associated fibroblast subtypes with implications
for tumor progression and response to therapy, for which we are now developing precision
targeting strategies using both small molecule inhibitors, antibodies and antibody-drug
conjugates.
The stromal compartment in general, and CAFs in particular, comprise a hitherto
underexploited source for factors harboring prognostic, predictive or therapeutic potential.
Taken together, our current work defines a sustainable framework for exploring and
implementing cellular microniches as drug targets and tools for precision cancer medicines.

Volkan Sayin, Sahlgrenska Center for Cancer Research, Inst. Clinical Sciences, University of Gothenburg, SE
https://www.gu.se/en/research/volkan-sayin

Aging, Metabolism and KRAS-driven Lung Cancer: Do Tumors in the Elderly Refuse Growing Up?
Lung cancer is primarily a disease of the elderly. Although aging and cancer share key molecular alterations – such as deregulated protein homeostasis and permissive chromatin states – studies using physiologically aged models of lung cancer are few. Here, we show that aging alters the progression of KRAS-driven non-small cell lung cancer (NSCLC), promoting metastasis while suppressing primary lung tumor growth. Primary lung tumor cultures derived from older mice demonstrated an increased metastatic phenotype. Unbiased multiomics identified ATF4, the main effector of the integrated stress response, as a driver of aging-induced lung cancer metastasis. Furthermore, we found that the age-associated increase in ATF4 fuels metastatic dissemination through metabolic rewiring, which constitutes druggable vulnerabilities. Clinically, a multicenter analysis of all consecutively diagnosed NSCLC cases in Western Sweden over a 3-year period confirmed increased metastasis and smaller primary tumor size with increasing age in KRAS-driven NSCLC. Our findings suggest a novel adjuvant therapy for human lung cancer by targeting aging-induced metabolic plasticity, highlighting the need to consider the biology of aging in the development of cancer therapy.

Sophia Harild, Umeå University, Department of Diagnostics and Intervention
https://www.umu.se/en/research/groups/sophia-harlid/

Environmental exposures during sensitive time periods
– a key to understanding breast cancer risk?
Windows of susceptibility are time-periods when we are especially vulnerable to environmental exposures. For women, these occur during fetal life, puberty, pregnancy, and menopause. One aim in my research, and the focus of this lecture, is identification of exposures occurring during these time periods, that are associated with later breast cancer risk. The talk touches on several ongoing projects: In the first I will describe work aiming to identify pregnancy exposures that are associated with premenopausal breast cancer. This will include new results from a nationwide study on air pollution exposure during pregnancy where we compared risk estimates depending on exposure timing. In the second project we are focusing on risk factors that may have a mediating role between exposure and cancer development including lactation-length and breast density. This is done in a new cohort (NorthMom) consisting of women that were part of an ongoing mother-child study in Västerbotten and therefore have provided detailed information on pregnancy exposures. As part of NorthMom we are also hoping to identify biomarkers that can inform us about previous exposures. Finally, I will briefly discuss future studies of exposures occurring during the perimenopausal window of susceptibility and later risk of postmenopausal breast cancer.

Research field: Molecular Epidemiology

Radiotherapy and Theranostics

Vladimir Tolmachev, Department of Immunology, Genetics and Pathology (IGP), Uppsala University
Email: vladimir.tolmachev@igp.uu.se

Radionuclide molecular targeting of cancer using engineered scaffold proteins
Targeted cancer treatment can extend patients survival, with outcomes often depending on the level of molecular targets expression. Radionuclide molecular imaging allows us to visualize these targets in malignant tumors, addressing their heterogeneity and changes over time.  Commonly, therapeutic antibodies are labeled with 89Zr for immunoPET visualization, but their bulkiness results in slow tumor localization and poor specificity, making imaging possible only 4 to 7 days post-injection.

We develop alternative imaging probes called engineered scaffold proteins (ESPs). ESP affibody molecules, ADAPTs, and DARPins for visualization of HER2 and EpCAM were evaluated in clinical trials.  Clinical trials have shown that these ESP are safe, well-tolerated, and deliver low absorbed doses. These agents offer better imaging sensitivity and specificity two to four hours post-injection compared to antibodies after 5 days. ESP-based probes visualizing EGFR, IGF-1R, HER3, CAIX, CEACAM5, VEGFR2, and B7-H3 are in preclinical development. In a quest for optimal labels, ESPs were labeled with 15 different nuclides for SPECT, and PET imaging. We found that a combination of a radionuclide and a chelator/linker for its coupling to ESP has a strong impact on the targeting properties of an ESP.

Preclinical studies demonstrate that ESP-based therapeutics can extend the survival of tumor-bearing mice by delivering cytotoxic nuclides. They can also deliver anti-cancer drugs or block mitotic signaling. Co-developing imaging companion diagnostics enables patient selection and treatment monitoring.

In conclusion, ESP-based targeting agents offer high affinity and specificity in vivo, are cheaper to produce than monoclonal antibodies, and allow radionuclide imaging within hours of injection. ESPs can be engineered for multispecific constructs with adjustable targeting properties, aiding the development of anti-tumor therapeutics with different mechanisms of action.

Neuroimmunooncology

Mattias Belting, Professor of Oncology, Consultant Neuro-Oncologist, Lund University
https://www.tumor-microenvironment.lu.se/tumor-microenvironment-0

Tumor associated foam cells in brain tumors offer new therapeutic avenues
Immune cell metabolic rewiring and adaptation are common phenomena in major human conditions, including neurodegeneration and atherosclerosis. Based on our findings, we introduce tumor-associated foam cells (TAFs), a previously uncharacterized immune cell entity of lipid droplet (LD)-loaded macrophages in GBM, an incurable and common tumor of the brain. Through extensive analyses of patient tumors, together with in vitro and in vivo investigations, we reveal that TAFs exhibit distinct pro-tumorigenic characteristics related to hypoxia, mesenchymal transition, angiogenesis, impaired phagocytosis, and their presence correlates with worse patient outcome. Our mechanistic investigations demonstrate that TAF formation is facilitated by lipid scavenging from extracellular vesicles released by GBM cells. Importantly, we demonstrate that targeting key enzymes involved in LD formation, such as DGAT1 or ACSL, effectively disrupts TAF functionality. Our studies establish TAFs as a prominent immune cell entity in GBM and provide valuable insights into their interplay within the microenvironment. Disrupting LD formation to target TAFs presents an interesting avenue for future therapeutic development in GBM.

Early detection and surveillance

Benny Björkblom, Department of Chemistry, Umeå University, Sweden.
Email: benny.bjorkblom@umu.se

Exploring Metabolic Markers for Early Detection and classification of Brain Tumors
Gliomas are highly complex and metabolically active brain tumors that are often diagnosed late, adversely affecting patient prognosis and quality of life. Our research aims to identify early metabolic changes in blood that could serve as biomarkers for glioma detection before clinical symptoms appear.
In our research, we have metabolically characterized pre-diagnostic blood samples from glioma cases and healthy controls in the Northern Sweden Health and Disease Study (NSHDS) and the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Our findings revealed significant metabolic alterations two to eight years before diagnosis, with a distinct panel of metabolites strongly associated with glioma development. These metabolic changes were consistent across biological sexes and enabled the differentiation of future glioma cases from controls. Specifically, we observed elevated levels of TCA-cycle-related metabolites, including fumarate, malate, lactate, N-lactoyl-amino acids, and pyruvate, highlighting increased energy turnover in early tumor development. At the time of surgery, amino acid metabolism was markedly altered, with high levels of amino acids and their catabolic byproducts, particularly branched-chain alpha-keto acids. These metabolic signatures were detectable in blood, underscoring their potential as non-invasive biomarkers for early glioma detection.
Our longitudinal analysis, incorporating blood samples from the same individuals collected both years before diagnosis and at surgery, identified both general and glioma subtype-specific metabolic changes. Also, here a subset of TCA-cycle-related metabolites demonstrated strong predictive potential for glioma presence both pre-diagnostically and at surgery. We believe that these findings may provide insights into the metabolic evolution of glioma, possibly paving the way for improved early detection strategies

Qiaoli Wang, Lund University & Karolinska Institutet
https://ki.se/personer/qiaoli-wang

Extracellular Vesicles (EVs)-Based Liquid Biopsy for Pancreatic Cancer Detection
Liquid biopsy using extracellular vesicles (EVs) has emerged as a promising non-invasive tool for cancer detection. EVs isolated from blood carries molecular cargo such as proteins reflective of their origins including cancer cells. Compared with traditional biomarkers such CA19-9 alone, EV-based assays could improve panel sensitivity and specificity, enabling earlier diagnosis of pancreatic cancer. This talk will focus on the EV-based based mucin expressions in plasma and its discriminative ability in early detection of pancreatic cancer. Dr. Wang’s lab is highlighted by the Integrative Pancreatic Cancer Research (iPanCare), with focus on developing strategies for precision prevention, early diagnosis, individual risk stratification, and personalized medicine approaches for pancreatic cancer by leveraging integrative approaches of genetic and molecular epidemiology, pharmaco-epidemiology, and machine learning using large-scale population-based cohorts, national registries, electronic healthcare records, and multi-center clinical studies. As an emerging research group, we actively seek collaborative partnerships with investigators whose expertise intersects with our core research foci in early detection and precision medicine of pancreatic cancer.

Advances in immunotherapy

Judit Svensson-Arvelund, Linköping University, SE
judit.arvelund@liu.se

Oncolytic virus-based immunotherapy for lymphoma: harnessing the power of dendritic cells
Advanced indolent non-Hodgkin’s lymphomas are incurable with standard therapy and are poorly responsive to immune checkpoint blockade. Since anti-tumor immunity depends on T cells that recognize tumor-antigens, immunotherapies have focused on increasing T cells at the effector phase, e.g., by blocking inhibitory signals through checkpoint blockade. While these strategies have been successful for some patients, they have limitations, such as the requirement for pre-existing tumor-reactive T cells. An alternative is to prime T cells at the tumor site by in situ vaccination (ISV) and harnessing the potential of dendritic cells (DCs) to cross-present tumor-antigens and induce anti-tumor immunity. An ISV can be generated through oncolytic viruses, which in addition to actively lysing tumor cells, release tumor-antigens and promote pro-inflammatory signals to induce anti-tumor immunity. We demonstrate that amplifying DCs in the context of an oncolytic virus-based ISV promotes durable tumor regressions and induction of tumor-reactive T cells that persist long-term in a murine lymphoma model. Our ongoing research aims to define the mechanisms of response versus resistance, and to determine the impacts of tumor heterogeneity and the tissue-specific microenvironments on therapy response. Our goal is to develop a safe and effective therapy that can overcome the limitations of current therapies.

Research field: Tumor immunology and Immunotherapy

AI, Data integration and multiomics

Tuuli Lappalainen, PhD, Science for Life Laboratory, Department of Gene Technology, KTH Royal Institute of Technology, Stockholm, Sweden
New York Genome Center, New York, USA
https://tllab.org

Functional variation in the human genome: lessons from the transcriptome
Detailed characterization of molecular and cellular effects of genetic variants is essential for understanding biological processes that underlie genetic associations to disease. A particularly scalable approach has been linking genetic variants to effects in the transcriptome, which is amenable for scalable measurements in human populations and in model systems, including at the single cell level. Here, I will describe recent advances in our long-term work to characterize genetic associations to the transcriptome and other molecular traits, as well as our recent work on CRISPR-based perturbation of gene expression levels in cellular models. Altogether, integrating insights from these diverse approaches uncovers functional genetic architecture of human traits and the molecular and cellular mechanisms that mediate these effects.