Decoding the interplay between genetic and non-genetic drivers of metastasis.

Metastasis is a multistep process by which cancer cells break away from their original location and spread to distant organs, and is responsible for the vast majority of cancer-related deaths. Preventing early metastatic dissemination would revolutionize the ability to fight cancer. Unfortunately, the relatively poor understanding of the molecular underpinnings of metastasis has hampered the development of effective anti-metastatic drugs.

Cell States in Cancer: Drivers, Passengers, and Trailers.

Summary: Cancer is traditionally perceived through a genetic lens, with therapeutic strategies targeting oncogenic driver mutations. We advocate an overarching framework recognizing tumors as comprising driver, passenger, and trailer cell states: Tailoring therapies to simultaneously target driver genetics and cell states may enhance effectiveness and durability.

Significance: We redefine cancer progression by introducing a model that categorizes tumor cells into "driver," "passenger," and "trailer" phenotypes, expanding the focus on genetic aberrations to cellular behavior.

Multimodal stimulation screens reveal unique and shared genes limiting T cell fitness.

Genes limiting T cell antitumor activity may serve as therapeutic targets. It has not been systematically studied whether there are regulators that uniquely or broadly contribute to T cell fitness. We perform genome-scale CRISPR-Cas9 knockout screens in primary CD8 T cells to uncover genes negatively impacting fitness upon three modes of stimulation: (1) intense, triggering activation-induced cell death (AICD); (2) acute, triggering expansion; (3) chronic, causing dysfunction.

A Mutation-driven oncofetal regression fuels phenotypic plasticity in colorectal cancer.

Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment . However, the molecular mechanisms underlying resistance to LGR5 CSCs depletion in colorectal cancer (CRC) remain largely elusive. Here, we unveil the existence of a primitive cell state dubbed the oncofetal (OnF) state, which works in tandem with the LGR5 stem cells (SCs) to fuel tumor evolution in CRC.

Cancer Evolution: A Multifaceted Affair.

Unlabelled: Cancer cells adapt and survive through the acquisition and selection of molecular modifications. This process defines cancer evolution. Building on a theoretical framework based on heritable genetic changes has provided insights into the mechanisms supporting cancer evolution.

Tumor endothelial cell autophagy is a key vascular-immune checkpoint in melanoma.

Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show that autophagy ablation in TECs boosts antitumor immunity by supporting infiltration and effector function of T-cells, thereby restricting melanoma growth.

Perivascular niches: critical hubs in cancer evolution.

Tumors are heterogeneous ecosystems in which cancer cells coexist within a complex tumor immune microenvironment (TIME). The malignant, stromal, and immune cell compartments establish a plethora of bidirectional cell-cell communication crosstalks that influence tumor growth and metastatic dissemination, which we are only beginning to understand. Cancer cells either co-opt or promote the formation of new blood and lymphatic vessels to cope with their need for nutrients and oxygen.

Melanoma-intrinsic NR2F6 activity regulates antitumor immunity.

Nuclear receptors (NRs) are implicated in the regulation of tumors and immune cells. We identify a tumor-intrinsic function of the orphan NR, NR2F6, regulating antitumor immunity. NR2F6 was selected from 48 candidate NRs based on an expression pattern in melanoma patient specimens (i.

The CD58-CD2 axis is co-regulated with PD-L1 via CMTM6 and shapes anti-tumor immunity.

The cell-autonomous balance of immune-inhibitory and -stimulatory signals is a critical process in cancer immune evasion. Using patient-derived co-cultures, humanized mouse models, and single-cell RNA-sequencing of patient melanomas biopsied before and on immune checkpoint blockade, we find that intact cancer cell-intrinsic expression of CD58 and ligation to CD2 is required for anti-tumor immunity and is predictive of treatment response. Defects in this axis promote immune evasion through diminished T cell activation, impaired intratumoral T cell infiltration and proliferation, and concurrently increased PD-L1 protein stabilization.

Apoptotic cell death in disease-Current understanding of the NCCD 2023.

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions.

Pharmacological induction of membrane lipid poly-unsaturation sensitizes melanoma to ROS inducers and overcomes acquired resistance to targeted therapy.

Background: One of the key limitations of targeted cancer therapies is the rapid onset of therapy resistance. Taking BRAF-mutant melanoma as paradigm, we previously identified the lipogenic regulator SREBP-1 as a central mediator of resistance to MAPK-targeted therapy. Reasoning that lipogenesis-mediated alterations in membrane lipid poly-unsaturation lie at the basis of therapy resistance, we targeted fatty acid synthase (FASN) as key player in this pathway to evoke an exquisite vulnerability to clinical inducers of reactive oxygen species (ROS), thereby rationalizing a novel clinically actionable combination therapy to overcome therapy resistance.

Glucocorticoid activation by HSD11B1 limits T cell-driven interferon signaling and response to PD-1 blockade in melanoma.

Background: Immune responses against tumors are subject to negative feedback regulation. Immune checkpoint inhibitors (ICIs) blocking Programmed cell death protein 1 (PD-1), a receptor expressed on T cells, or its ligand PD-L1 have significantly improved the treatment of cancer, in particular malignant melanoma. Nevertheless, responses and durability are variables, suggesting that additional critical negative feedback mechanisms exist and need to be targeted to improve therapeutic efficacy.

An adverse tumor-protective effect of IDO1 inhibition.

By restoring tryptophan, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors aim to reactivate anti-tumor T cells. However, a phase III trial assessing their clinical benefit failed, prompting us to revisit the role of IDO1 in tumor cells under T cell attack. We show here that IDO1 inhibition leads to an adverse protection of melanoma cells to T cell-derived interferon-gamma (IFNγ).

A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling.

Metabolic rewiring is often considered an adaptive pressure limiting metastasis formation; however, some nutrients available at distant organs may inherently promote metastatic growth. We find that the lung and liver are lipid-rich environments. Moreover, we observe that pre-metastatic niche formation increases palmitate availability only in the lung, whereas a high-fat diet increases it in both organs.

is commonly amplified and high expression in cancer cells correlates with poor immune checkpoint blockade response.

Immunotherapies, in particular immune checkpoint blockade (ICB), have improved the clinical outcome of cancer patients, although many fail to mount a durable response. Several resistance mechanisms have been identified, but our understanding of the requirements for a robust ICB response is incomplete. We have engineered an MHC I/antigen: TCR-matched panel of human NSCLC cancer and T cells to identify tumor cell-intrinsic T cell resistance mechanisms.