Despite an initially effective treatment response and the use of new targeted and immune-based therapeutic approaches, the prognosis of patients with metastatic cancers remains poor due to therapy-resistant relapses. Improved treatment strategies are therefore urgently needed for these patients. To this end, a key question addressed in the Cancer-Stroma Crosstalk group, headed by Professor Kaisa Lehti, is: How do we more effectively eliminate heterogenous (micro)metastases with capacity to sustain tumor evolution and recurrent growth through cancer- and stroma-dependent mechanisms of therapy-escape? 

Combinatorial tumor-microenvironment targeting and ex vivo tissue-based drug testing to eradicate metastatic cancers

In addition to the inherent malignant properties of tumor cells, a cancer-promoting tumor microenvironment (TME; also called tumor stroma) is necessary for cancer cells to survive and grow in distinct organs. This interplay between the tumor cell and TME drives metastatic cancer progression and therapy resistance. Recent results from Lehti’s group and others demonstrate that both the tumor and TME are altered following chemotherapy and other treatments, which can further facilitate the growth or invasion of the residual cancer cells, thus paradoxically promoting the tumor recurrence. However, the exact mechanisms underpinning these processes remain elusive. By uncovering such mechanisms, the Cancer-Stroma Crosstalk group aims to employ combinatorial therapeutic strategies to block the malignant TME communication and metastatic tumor evolution. 

The group has a longstanding interest in the variable molecular mechanisms of cancer invasion, metastasis, and therapy resistance in the evolving TME.

To date, their results have revealed unique molecular mechanisms such as:

1. The co-evolution of chemoresistance-driving fibrotic extracellular matrix (ECM) with the ECM composition- and stiffness-dependent adhesion signaling
2. TME-dependent oncogenic receptor tyrosine kinase signaling
3. Transmembrane protease –signaling receptor crosstalk in both stroma and cancer cells. 

Translational TME research is based on concepts that metastasis- or drug resistance-promoting tumor-TME communication can be blocked, and even the initially tumor-suppressive TME can be re-exposed. In the Cancer-Stroma Crosstalk group, this is considered achievable by furthering the fundamental knowledge on tumor fibrosis, ECM remodeling, inflammatory pathways, and immune evasion. Given the emerging connections between the tumor ECM, immune landscape, and poor patient survival, this increased understanding will provide opportunities to ‘rewire’ these mechanisms to prevent a pro-tumor microenvironment, thereby preventing therapy-resistant relapses.

Here the recent insights on biochemical and physical TME properties and cancer cell signaling form the basis for both the translational Norwegian Cancer Society (Kreftforeningen) project as well as the basic, molecular mechanistic TME signaling research in the group (Pietila et al NatureComms 2021; Moyano-Galzeran et al Embo MM 2020; Turunen et al Cell Death Differ 2019). 

Altogether, this research aims to answer the following key questions: 

1. How do tumor metastasis and therapy alter mechanisms of TME communication via fibro-inflammatory factors and ECM signaling? 
2. Which of these alterations affect progression and acquired therapy resistance of ovarian cancer, and other cancers, by mechanisms related to tumor evolution and phenotypic plasticity? 
3. Can the above-identified pathways and mechanisms be translated to new biomarkers and combinatorial treatment strategies for improved therapy?

Clinically significant results are ensured by employing cutting-edge technologies for primary cancer and stromal cell isolation, ex vivo 3D cell, organoid and tissue culture, in vivo tumor models, and close collaboration with clinicians and clinical scientists at St Olavs Hospital (coordinated with Associate Professors Guro Aune and Marit Valla) and other Scandinavian university hospitals. Therefore, the gained results will contribute to the comprehensive understanding of TME communication and metastatic cancer progression with potential implications to the development of improved diagnostic tools and treatment options.