Steatotic Liver Promotes Metastatic Niche: Role of Hepatic Stellate Cells

Cedars-Sinai Medical Center, West Hollywood CA

Investigators

Abstract

PROJECT SUMMARY Liver metastasis is a major survival determinant for patients with gastrointestinal cancers, such as colorectal (CRC) and pancreatic ductal adenocarcinoma (PDAC). Obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) are serious health concerns that increase the risks of primary cancers and liver metastasis in cancer patients. In rodents, feeding a high-fat diet accelerates liver metastases in CRC and PDAC. With the prevalence of MASLD increasing, the incidence of liver metastasis in patients is expected to rise. We will investigate the molecular mechanisms underlying the fibrotic microenvironment modulated by MASLD and determine immunomodulatory mechanisms that promote liver metastasis. Hepatic stellate cells (HSCs) in the liver with metastasis are comprised of intra-tumoral HSCs and extra-tumoral HSCs. Intra-tumoral HSCs affect the progression of PDAC and CRC liver metastasis via the production of extracellular matrix (ECM) and other factors. Our preliminary data show that MASLD-associated extra-tumoral HSCs are the main producer of pro-tumorigenic CXCL12. We hypothesize that extra-tumoral HSC-derived CXCL12 activates cancer cells, intra-tumoral HSCs, and neutrophils via CXCR4 and Yes-associated protein (YAP), and that intra-tumoral HSC-derived ECM and ECM modulated by neutrophil PAD4 yield a pro-metastatic microenvironment that is enhanced by a high-fat diet-mediated MASLD. To test our hypothesis, we will investigate the differential roles of extra-tumoral HSCs and intra-tumoral HSCs, and the effect of intra-tumoral HSC-derived ECM and ECM modification in the progression of liver metastasis with MASLD through three specific aims. Aim 1 will investigate the regulatory mechanism and functional role of extra-tumoral HSCs in liver metastasis with MASLD by studying CXCL12 upregulated in HSCs from non-tumor livers. Aim 2 will investigate the role of intra-tumoral HSCs and ECM in the CXCR4-YAP axis in liver metastasis with MASLD. Aim 2 will also investigate the mechanism of CXCR4 activation by ECM and YAP in cancer. Aim 3 will investigate whether ECM modification by protein citrullination affects metastatic activity in MASLD. Aim 3 will also test if PAD4 inhibition improves the anti-cancer effect of anti-PD1 therapy to determine the mechanism of the ineffectiveness of anti- PD1 therapy for metastasis in MASLD. Our study will reveal the understudied roles of extra-tumoral HSCs and intra-tumoral HSCs, and the effect of post-translational modification of ECM in liver metastasis progression in MASLD. This study proposes a new clinically relevant paradigm that supports the differential management of liver metastasis in patients with and without MASLD.