Patricia Altea-Manzano

Acute myeloid leukemia (AML) is driven by genetic alterations and non-mutational mechanisms that disrupt normal hematopoiesis and support leukemic cell survival. While the mutational landscape of AML is well characterized, the non-genetic processes sustaining leukemic maintenance remain less understood. Using human AML cells and murine models, we identify BCL2-associated transcription factor 1 (BCLAF1) as a key regulator of leukemic progression through control of mRNA processing. BCLAF1 physically associates with core spliceosome components and regulates alternative splicing programs in leukemic cells. Mechanistically, BCLAF1 is required for productive splicing of activating transcription factor 4 (ATF4) mRNA, thereby sustaining ATF4 protein levels and downstream metabolic gene expression programs. Loss of BCLAF1 reduces ATF4 levels, leading to impaired de novo amino acid biosynthesis and increased sensitivity to venetoclax. Together, these findings uncover a previously unrecognized mechanism linking RNA splicing control to metabolic adaptation in AML, identifying BCLAF1 as a potential therapeutic vulnerability.

Metastasis is responsible for the vast majority of cancer‐related deaths, yet organ selectivity and the fate of disseminated cancer cells remain incompletely understood. While tumor‐intrinsic programs have been extensively characterized, increasing evidence indicates that host‐related extrinsic factors critically modulate the molecular and cellular landscape of metastatic niches. Aging, dietary habits, microbiome, physical activity, smoking, air pollution, and chronic stress may reshape systemic inflammation, immune surveillance, vascular permeability, stromal composition, extracellular matrix remodeling, and metabolic signaling in organs commonly targeted by metastasis, including bone, lung, liver, and brain. These host‐dependent alterations influence disseminated cancer cell homing, extravasation, dormancy, and proliferative outgrowth by reprogramming tissue‐resident and recruited cell populations, as well as niche‐derived soluble and mechanical cues. In this review, we describe a framework in which metastasis is dynamically codetermined by tumor cell plasticity and host systemic state, contextualized by recent mechanistic insights into how lifestyle and physiological states rewire organ microenvironments to become either permissive or restrictive to metastatic colonization. Understanding these interactions may reveal actionable targets for metastasis prevention and highlight modifiable behaviors as biological determinants of organ susceptibility to metastatic disease.

Cancer cells that seed in the lung require lipids often produced by alveolar type II (AT2) cells. However, whether overt metastases depend on AT2 cell–derived lipids and whether AT2 cells can be targeted to reduce metastasis growth remains unknown. We discovered that breast cancer–derived lung metastases stimulate the proliferation of AT2 cells in their vicinity and reprogram them into lipid feeder cells in mice and patients using spatial analysis. Mechanistically, the metastasis secretome activates the transcription factor sterol regulatory element–binding transcription factor 1 (SREBP-1) in AT2 cells, enhancing the expression of key de novo lipid synthesis genes, including fatty acid synthase (FASN) and glycerol-3-phosphate acyltransferase 1 (GPAM). Deleting Fasn selectively in AT2 cells or targeting FASN and GPAM systemically significantly impairs lung metastasis growth in mice. In summary, we discovered that overt metastases reprogram AT2 cells and that targeting the lipid metabolism of AT2 cells impairs metastasis growth.Significance:Current therapies in oncology targeting the cancer or immune cell compartment of tumors show limited efficacy against breast cancer–derived metastases. We discovered that decreasing the lipid metabolism of lung resident AT2 cells is sufficient to impair lung metastasis growth in mice without apparent adverse effects.

Supplementary Figure 1 Surfactant lipids are enriched in the vicinity of lung metastases from patients with breast cancer; Supplementary Figure 2 AT2 cells and surfactant lipids co-localize in the vicinity of metastases from mice; Supplementary Figure 3 Metastases progression increases the enrichment of AT2 cells; Supplementary Figure 4 The metastasis secretome reprograms AT2 cell lipid metabolism by activating SREBP-1; Supplementary Figure 5 Gpam knockdown in cancer cells does not affect 3D spheroid growth in vitro; Supplementary Figure 6 GPAM and FASN inhibition in cancer cells does not affect metastasis formation in vitro and in vivo

Short hairpin RNAs (shRNAs) used to generate knockdown cell lines

Acetylation is frequently dysregulated in cancer, and both acetyltransferase and deacetylase inhibitors are being evaluated at various stages of preclinical and clinical development. However, how the expression of acetyltransferases and deacetylases is regulated remains often elusive. We focused on the lysine acetyltransferase 2A (KAT2A) as it is important in multiple cancer indications with a clinical inhibitor in development. We discovered that KAT2A expression is regulated by palmitoylation in breast cancer-derived metastases. Specifically, we find that the palmitoyltransferase DHHC20 (gene name ZDHHC20) palmitoylates transmembrane 4L six family member 1 (TM4SF1) promoting its plasma membrane localization. This in turn fosters phosphorylation of the signal transducer and activator of transcription 3 (STAT3), which we identify as a transcriptional regulator of KAT2A. Accordingly, Zdhhc20 and Tm4sf1 silencing as well as expression of a Tm4sf1 double palmitoylation mutant decreases lung metastasis growth, which is rescued by Kat2a expression. We detect evidence of this palmitoylation-induced regulation of KAT2A in lung metastasis samples from patients with breast cancer. Thus, we show that palmitoylation can orchestrate the expression of a global acetylation regulator in lung metastases.

Cancer cells that seed in the lung require lipids often produced by alveolar type II (AT2) cells. However, whether overt metastases depend on AT2 cell–derived lipids and whether AT2 cells can be targeted to reduce metastasis growth remains unknown. We discovered that breast cancer–derived lung metastases stimulate the proliferation of AT2 cells in their vicinity and reprogram them into lipid feeder cells in mice and patients using spatial analysis. Mechanistically, the metastasis secretome activates the transcription factor sterol regulatory element–binding transcription factor 1 (SREBP-1) in AT2 cells, enhancing the expression of key de novo lipid synthesis genes, including fatty acid synthase (FASN) and glycerol-3-phosphate acyltransferase 1 (GPAM). Deleting Fasn selectively in AT2 cells or targeting FASN and GPAM systemically significantly impairs lung metastasis growth in mice. In summary, we discovered that overt metastases reprogram AT2 cells and that targeting the lipid metabolism of AT2 cells impairs metastasis growth. Significance: Current therapies in oncology targeting the cancer or immune cell compartment of tumors show limited efficacy against breast cancer–derived metastases. We discovered that decreasing the lipid metabolism of lung resident AT2 cells is sufficient to impair lung metastasis growth in mice without apparent adverse effects.