The mechanisms that allow breast cancer (BCa) cells to metabolically sustain rapid growth are poorly understood. Here we report that BCa cells are dependent on a mechanism to supply precursors for intracellular lipid production derived from extracellular sources and that the endothelial lipase (LIPG) fulfils this function. LIPG expression allows the import of lipid precursors, thereby contributing to BCa proliferation. LIPG stands out as an essential component of the lipid metabolic adaptations that BCa cells, and not normal tissue, must undergo to support high proliferation rates. LIPG is ubiquitously and highly expressed under the control of FoxA1 or FoxA2 in all BCa subtypes. The downregulation of either LIPG or FoxA in transformed cells results in decreased proliferation and impaired synthesis of intracellular lipids.

Colorectal cancers (CRCs) are composed of an amalgam of cells with distinct genotypes and phenotypes. Here we reveal a previously unappreciated heterogeneity in the biosynthetic capacities of CRC cells. We discover that the majority of ribosomal DNA transcription and protein synthesis in CRCs occur in a limited subset of tumor cells that localize in defined niches. The rest of the tumor cells undergo an irreversible loss of their biosynthetic capacities as a consequence of differentiation. Cancer cells within the biosynthetic domains are characterized by elevated levels of the RNA Polymerase 1 subunit A -POLR1A. Genetic ablation of POLR1A-high cell population imposes an irreversible growth arrest to CRCs. We show that elevated biosynthesis defines stemness in both LGR5+ and LGR5-tumor cells. Therefore, a common architecture in CRC is a simple cell hierarchy based on the differential capacity to transcribe ribosomal DNA and synthesize proteins.

Glycogenin is considered essential for glycogen synthesis, as it acts as a primer for the initiation of the polysaccharide chain. Against expectations, glycogenin-deficient mice (Gyg KO) accumulate high amounts of glycogen in striated muscle. Furthermore, this glycogen contains no covalently bound protein, thereby demonstrating that a protein primer is not strictly necessary for the synthesis of the polysaccharide in vivo. Strikingly, in spite of the higher glycogen content, Gyg KO mice showed lower resting energy expenditure and less resistance than control animals when subjected to endurance exercise. These observations can be attributed to a switch of oxidative myofibers toward glycolytic metabolism. Mice overexpressing glycogen synthase in the muscle showed similar alterations, thus indicating that this switch is caused by the excess of glycogen. These results may explain the muscular defects of GSD XV patients, who lack glycogenin-1 and show high glycogen accumulation in muscle.

40% of colorectal cancer (CRC) patients undergoing curative resection of the primary tumor will develop metastases in the following years 1 . Therapies to prevent disease relapse remain an unmet medical need. Here we uncover the identity and features of the residual tumor cells responsible for CRC relapse. Analysis of single-cell transcriptomes of CRC patient samples revealed that the majority of poor prognosis genes are expressed by a unique tumor cell population that we named High Relapse Cells (HRCs). We established a human-like mouse model of microsatellite stable CRC that undergoes metastatic relapse following surgical resection of the primary tumor. Residual HRCs occult in mouse livers after primary CRC surgery gave rise to multiple cell types over time, including Lgr5+ stemlike tumor cells 2-4 , and caused overt metastatic disease. Using Emp1 (epithelial membrane Competitiveness (MINECO). HH is a Miguel Servet (CP14/00229) researcher funded by the

The standard of care for advanced colorectal cancer (CRC) includes treatment with chemotherapeutic drugs that target the cell proliferation machinery 1 . In CRC patients with overt metastases, chemotherapy initially halts tumor growth but, almost inevitably, disease progresses after some cycles of treatment. Adjuvant chemotherapy is also administered to eliminate minimal residual disease, yet it only diminishes the risk of relapse by 10-25% 2 . Previous studies have shown that patient-derived organoids predict responses to chemotherapy 3-6 . Therefore, we used them as models to investigate the mechanisms behind the limited benefit of these treatments. Whereas CRC organoids expand from highly proliferative Lgr5+ tumor cells, we discovered that lack of optimal stem cell growth conditions specifies a latent Lgr5+ cell population. These cells expressed the gene Mex3a, were largely insensitive to chemotherapy and regenerated the organoid culture after treatment. In mouse models of metastatic latency, Mex3a+ cells contributed marginally to metastatic outgrowth. However, after chemotherapy treatment, Mex3a+ cells produced large cell clones that regenerated metastatic disease. Using lineage-tracing analysis combined with single cell profiling, we showed that drug-tolerant persister Mex3a+ cells downregulate the WNT/Lgr5+ stem cell program immediately after chemotherapy and adopt a transient regenerative state