Nature Reviews Gastroenterology &Hepatology最新文献

New research published in Science Translational Medicine identifies an interplay between tumour-intrinsic and tumour-extrinsic factors that drive resistance to treatment in pancreatic ductal adenocarcinoma (PDAC). The findings provide the rationale for combined therapies that target both oncogenic signalling and the tumour microenvironment to overcome PDAC drug resistance.

Inhibitors of the RAS–MAPK pathway hold great promise as a therapeutic strategy for PDAC. However, patients rapidly develop drug resistance, explained in part by upregulation of members of the receptor tyrosine kinase family. The researchers found that the combination of RAS–MAPK inhibitors with inhibitors of focal adhesion kinase (FAK) — a non-receptor tyrosine kinase — reduced tumour growth and increased survival in several mouse models of PDAC to a greater extent than either therapy alone. Single-cell RNA sequencing and cell culture experiments revealed that cancer-associated fibroblasts in the tumour microenvironment are activated by FAK and impair the downregulation of MYC by RAS–MAPK inhibition in PDAC cells, resulting in drug resistance. “This identifies cancer-associated fibroblasts as a novel therapeutic target for overcoming RAS pathway resistance,” explains author Gregory Beatty.

Visceral pain is a major clinical problem and one of the most common reasons patients with gastrointestinal disorders seek medical help. Peripheral sensory neurons that innervate the gut can detect noxious stimuli and send signals to the central nervous system that are perceived as pain. There is a bidirectional communication network between the gastrointestinal tract and the nervous system that mediates pain through the gut–brain axis. Sensory neurons detect mechanical and chemical stimuli within the intestinal tissues, and receive signals from immune cells, epithelial cells and the gut microbiota, which results in peripheral sensitization and visceral pain. This Review focuses on molecular communication between these non-neuronal cell types and neurons in visceral pain. These bidirectional interactions can be dysregulated during gastrointestinal diseases to exacerbate visceral pain. We outline the anatomical pathways involved in pain processing in the gut and how cell–cell communication is integrated into this gut–brain axis. Understanding how bidirectional communication between the gut and nervous system is altered during disease could provide new therapeutic targets for treating visceral pain.

A new study published in Nature explores the dynamic changes that colorectal cancer (CRC) cells undergo during their transition to the metastatic state by comparing primary tumours with metastases. “Clinically, metastases are less responsive to therapy than primary tumours in the same patients, despite harbouring the same mutations,” says Karuna Ganesh, co-corresponding author of the study.

The researchers collected trios of same-patient biopsy samples of normal colon, primary and metastatic tissue from 31 patients with microsatellite-stable mismatch-repair-proficient CRC undergoing synchronous colectomy and liver metastasectomy for metastatic CRC treatment. “We applied computational algorithms to single-cell RNA-sequencing collected from each trio to identify a series of conserved intermediate steps during the transition to the metastatic steps, including a reversion to an earlier fetal-like state along the transition,” says co-corresponding author Dana Pe’er.

To define the pathophysiology of metabolic dysfunction-associated steatotic liver disease (MASLD) and identify therapeutic options, it is crucial to understand the sources of hepatic fat accumulation. In patients with MASLD, it is estimated that hepatic triglycerides are primarily derived from adipose tissue as free fatty acids (~59%), followed by de novo lipogenesis (~26%) and diet (~15%). However, in 2012, through a series of radiolabelled tracer experiments in mice, van der Veen and colleagues reported for the first time in vivo that hepatic phosphatidylcholines (PCs; a major lipid component of cell membranes and lipoproteins) accounted for a staggering 65% of the hepatic triglyceride pool, challenging the existing understanding of adipose tissue free fatty acids as the primary provider of liver triglycerides, at least in mice. Specifically, the researchers found that high-density lipoprotein (HDL) PCs could account for approximately 50% of the hepatic PC pool and that one-third of the hepatic triglyceride pool could derive from HDL–PC, a finding that was reported as unexpected.

The study was elegantly performed, using a combination of wild-type and knockout mouse models, along with primary mouse hepatocytes, to provide multiple layers of evidence supporting the results. Despite the robustness and importance of the findings, the study has been largely overlooked by the liver research community. Motivated by these unexpected results, and the lack of studies on the HDL lipidome in humans across the MASLD spectrum, part of my PhD was dedicated to filling this knowledge gap.

Lymphatic vessels are crucial for fluid absorption and the transport of peripheral immune cells to lymph nodes. However, in the small intestine, the lymphatic fluid is rich in diet-derived lipids incorporated into chylomicrons and gut-specific immune cells. Thus, intestinal lymphatic vessels have evolved to handle these unique cargoes and are critical for systemic dietary lipid delivery and metabolism. This Review covers mechanisms of lipid absorption from epithelial cells to the lymphatics as well as unique features of the gut microenvironment that affect these functions. Moreover, we discuss details of the intestinal lymphatics in gut immune cell trafficking and insights into the role of inter-organ communication. Lastly, we highlight the particularities of fat absorption that can be harnessed for efficient lipid-soluble drug distribution for novel therapies, including the ability of chylomicron-associated drugs to bypass first-pass liver metabolism for systemic delivery. In all, this Review will help to promote an understanding of intestinal lymphatic–systemic interactions to guide future research directions.