Marco Gerling

Metastases are the main cause of cancer mortality. In liver metastases, prognosis depends on the histological pattern of the invasion front: Extensive tumor-hepatocyte contact is linked to inferior outcome, while a perimetastatic stromal capsule predicts favorable survival, suggesting critical differences in tumor invasion.  We study the biology of metastatic invasion in mice and patient samples. Recently, we have shown that encapsulation represents a failure of tumor cells to invade the liver plates, resulting in liver repair. Using single-cell interaction mapping, we uncovered that active invasion induces liver injury, mounting in the exhaustion of injury-induced transdifferentiated hepatocytes towards the tumor center.Based on these data, we hypothesize that liver injury in metastases is a double-edged sword, promoting either tumor invasion or liver repair.Here, we propose generating a cell-level spatiotemporal map of the events from active via impaired invasion to encapsulation. Using mouse models and single-cell sequencing, we will identify the cell types and signaling pathways that regulate the balance between tumor invasion and liver reparation. Selected pathways will be confirmed in human material, followed by functional assays to target tumor invasion in vivo and in heterotypic spheroid cultures.The expected outcome is a wiring diagram of the cellular facilitators and inhibitors of metastatic invasion, ultimately leading to novel ways to inhibit metastases growth.

Advancing personalized approaches in cancer therapy, aiding identification and adaptation of multi-modal treatment strategies for improved outcomes depends on clinical implementation of novel diagnostic technologies. For most cancer types the risk-features used to select individuals for post-operative adjuvant multimodal therapy are suboptimal, where many patients are overtreated and others undertreated. Liquid biopsy has opened a new diagnostic avenue to detect and monitor minimal residual disease (MRD) in individual cancer patients, especially for selecting patients for multi-modal therapies post-operatively. However, despite many circulating tumor DNA (ctDNA) diagnostics being developed there is a lack of standardization, harmonization, and robust data to demonstrate clinical validity. GUIDE.MRD is a consortium of leading academics, technology companies, pharmaceutical companies, and experts in multi-stakeholder engagements. Together, we will tackle the critical questions by developing reference standards for ctDNA diagnostics, clinically validate promising ctDNA diagnostics and develop data to guide the use of multi-modal therapies with a non-invasive diagnostic test. With robust engagement with regulatory authorities, payers and importantly patients themselves, we will develop recommendations and guidelines based on objective data to use ctDNA diagnostics to guide multi-modal therapy selection to improve patient outcomes.

Colon and rectal cancer is our third most common form of cancer and about a third are diagnosed with daughter tumors in the liver - liver metastases. Despite advances in surgery and oncology, spread to the liver means a significantly worse prognosis with shorter survival. Cancer cells in the liver grow by replacing healthy liver cells and then use the liver's own vascular system. The cancer cells' ability to replace healthy tissue can be assessed under the microscope, by studying the metastases invasion front. We and others have shown that the better the cancer cells are at replacing healthy liver cells, the worse the prognosis for the patient. Our research group studies the basic mechanisms that control how cancer cells replace healthy liver cells. We use mouse models in combination with a new method to map the gene expression of individual cells. With these experiments, we have identified a new type of liver cell that communicates directly with the tumor cells. These results have allowed us to now for the first time map the signaling pathways that control tumor invasion in metastases. In this project, we want to apply this new knowledge about how the metastases grow to improve the risk assessment and ultimately the treatment for patients with liver metastases from colon and rectal cancer. We will map the significance of the new liver cell we have identified both with animal experiments and by analyzing tissue from our patients. For this, we have collected data on patients who were operated on for liver metastases at Karolinska Hospital and established collaborations with international research groups and now have data from several thousand patients. We hope that the results can lead to clinically useful markers that would improve and individualize the management and choice of treatment for these patients, as well as contribute to new medical treatments that prevent the cancer cells from replacing healthy liver cells.

Stromal cells strongly affect differentiation and proliferation of tumor cells. Previously, I have identified Hedgehog (Hh) signaling as stromal tumor suppressor in colorectal cancer (CRC), repressing mesenchymal factors that control the epithelial stem cell state.Liver metastases are the main cause of death in CRC, but little is known of the metastatic stroma. Preliminary data indicate that in CRC liver metastases (CRLM), the stroma is highly heterogeneous: Hh target genes are induced adjacent to more differentiated tumor cells, while secreted stem cell factors define a different stromal population located at the invasion front.This project aims to decipher the roles of stromal niches in metastases. To this end, we will analyze human CRLM using multiplex RNA in situ hybridization and a novel single-cell RNA sequencing method designed to deconvolute cell-cell interactions. For functional validation of known and novel stromal factors, we will use genetically engineered mice to alter stromal signaling, as well as mouse and human organoids to manipulate CRLM ex vivo. In extended studies, we will apply these tools to investigate metastasis in other tumor types such as breast and pancreatic carcinomas.We aim to identify stromal therapeutic targets to inhibit metastatic progression. The results are expected to unveil principles of metastasis with the potential to benefit the increasing number of patients with metastatic disease, for whom targeted therapies are urgently needed.