Mitophagy in Intestinal Epithelial Cells Triggers Adaptive Immunity during Tumorigenesis.

In colorectal cancer patients, a high density of cytotoxic CD8+ T cells in tumors is associated with better prognosis. Using a Stat3 loss-of-function approach in two wnt/ß-catenin-dependent autochthonous models of sporadic intestinal tumorigenesis, we unravel a complex intracellular process in intestinal epithelial cells (IECs) that controls the induction of a CD8+ T cell based adaptive immune response. Elevated mitophagy in IECs causes iron(II)-accumulation in epithelial lysosomes, in turn, triggering lysosomal membrane permeabilization. Subsequent release of proteases into the cytoplasm augments MHC class I presentation and activation of CD8+ T cells via cross-dressing of dendritic cells. Thus, our findings highlight a so-far-unrecognized link between mitochondrial function, lysosomal integrity, and MHC class I presentation in IECs and suggest that therapies triggering mitophagy or inducing LMP in IECs may prove successful in shifting the balance toward anti-tumor immunity in colorectal cancer.

Mesenchymal Cells in Colon Cancer.

Mesenchymal cells in the intestine comprise a variety of cell types of diverse origins, functions, and molecular markers. They provide mechanical and structural support and have important functions during intestinal organogenesis, morphogenesis, and homeostasis. Recent studies of the human transcriptome have revealed their importance in the development of colorectal cancer, and studies from animal models have provided evidence for their roles in the pathogenesis of colitis-associated cancer and sporadic colorectal cancer. Mesenchymal cells in tumors, called cancer-associated fibroblasts, arise via activation of resident mesenchymal cell populations and the recruitment of bone marrow-derived mesenchymal stem cells and fibrocytes. Cancer-associated fibroblasts have a variety of activities that promote colon tumor development and progression; these include regulation of intestinal inflammation, epithelial proliferation, stem cell maintenance, angiogenesis, extracellular matrix remodeling, and metastasis. We review the intestinal mesenchymal cell-specific pathways that regulate these processes, with a focus on their roles in mediating interactions between inflammation and carcinogenesis. We also discuss how increasing our understanding of intestinal mesenchymal cell biology and function could lead to new strategies to identify and treat colitis-associated cancers.

Report from the first Tanzania Liver Cancer Conference: a call for action to unite in the fight against liver cancer in Sub-Saharan Africa, 17-18 March 2023, Dar es Salaam, Tanzania.

The first Tanzania Liver Cancer Conference (TLCC2023) took place on 17-18 March 2023 in Dar es Salaam, Tanzania with the aim of raising awareness among healthcare providers on the problem that liver cancer poses to the Tanzanian population and the urgent need to address this important issue. The conference focused on the following agenda items: 1) to build awareness among local healthcare providers on the status of liver cancer in Tanzania and the available diagnostic and management options, 2) to update Tanzanian healthcare providers on the current standard of care for liver cancer provided in developed countries and recent advancements in liver cancer care and 3) to promote an inclusive and multidisciplinary approach in research and the clinical care of patients with liver cancer in Tanzania. TLCC2023 was preceded by community-facing pre-conference activities, including screening 684 community members for hepatitis B virus free of charge. The conference was attended by 161 healthcare professionals from varying disciplines across Tanzania and abroad. TLCC2023 featured over 30 speakers from Tanzania, Kenya, Egypt, India and the United States that comprehensively covered a wide range of topics related to research and clinical care of liver cancer patients. A holistic and unified approach integrating both private and public sectors is vital in improving care for patients with liver cancer, and this was a common theme ingrained in the majority of presentations. Overall, the conference was well-received by attendees and knowledge assessment scores improved from 50% pre-conference to 75% post-conference (p < 0.001), demonstrating its educational value. As Tanzania's first conference on the subject, TLCC2023 marked an important milestone in a united fight against liver cancer in the country and beyond.

IKKß acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis.

Cancer-associated fibroblasts (CAFs) comprise one of the most important cell types in the tumor microenvironment. A proinflammatory NF-κB gene signature in CAFs has been suggested to promote tumorigenesis in models of pancreatic and mammary skin cancer. Using an autochthonous model of colitis-associated cancer (CAC) and sporadic cancer, we now provide evidence for a tumor-suppressive function of IKKß/NF-κB in CAFs. Fibroblast-restricted deletion of Ikkß stimulates intestinal epithelial cell proliferation, suppresses tumor cell death, enhances accumulation of CD4(+)Foxp3(+) regulatory T cells, and induces angiogenesis, ultimately promoting colonic tumor growth. In Ikkß-deficient fibroblasts, transcription of negative regulators of TGFß signaling, including Smad7 and Smurf1, is impaired, causing up-regulation of a TGFß gene signature and elevated hepatocyte growth factor (HGF) secretion. Overexpression of Smad7 in Ikkß-deficient fibroblasts prevents HGF secretion, and pharmacological inhibition of Met during the CAC model confirms that enhanced tumor promotion is dependent on HGF-Met signaling in mucosa of Ikkß-mutant animals. Collectively, these results highlight an unexpected tumor suppressive function of IKKß/NF-κB in CAFs linked to HGF release and raise potential concerns about the use of IKK inhibitors in colorectal cancer patients.

IKKα promotes intestinal tumorigenesis by limiting recruitment of M1-like polarized myeloid cells.

The recruitment of immune cells into solid tumors is an essential prerequisite of tumor development. Depending on the prevailing polarization profile of these infiltrating leucocytes, tumorigenesis is either promoted or blocked. Here, we identify IκB kinase α (IKKα) as a central regulator of a tumoricidal microenvironment during intestinal carcinogenesis. Mice deficient in IKKα kinase activity are largely protected from intestinal tumor development that is dependent on the enhanced recruitment of interferon γ (IFNγ)-expressing M1-like myeloid cells. In IKKα mutant mice, M1-like polarization is not controlled in a cell-autonomous manner but, rather, depends on the interplay of both IKKα mutant tumor epithelia and immune cells. Because therapies aiming at the tumor microenvironment rather than directly at the mutated cancer cell may circumvent resistance development, we suggest IKKα as a promising target for colorectal cancer (CRC) therapy.