Biology subjects

Chocarro-Calvo, A.

Publications and source records attributed to Chocarro-Calvo, A..

5 recordsLinked to original sources

bioRxiv2025

Metabolic buffering suppresses phenotype switching in cancer

The impact of the microenvironment on epigenetically plastic cancer cells underpins phenotypic heterogeneity, a major cause of metastatic dissemination and therapy resistance that together represent the primary cause of cancer-related death. Nutrient limitation is a key microenvironmental stress that can cause a phenotypic transition from proliferation to invasion via activation of the integrated stress response. However, whether and how the capacity to store and mobilize nutrients impacts phenotype-switching through metabolic buffering remains unknown. Here, using melanoma as a model, we reveal that the ability to accumulate and mobilize glycogen, that buffers glucose availability, plays a key role in phenotypic transitions in melanoma. While proliferative phenotype cells exhibit high levels of glycogen, invasion is marked by low glycogen levels. Significantly, an inability to store and metabolize glycogen leads to phenotype instability and a switch to invasion. Accordingly, glycogen levels inversely correlate with Clark levels in primary melanomas, with low expression of the glycogen phosphorylases PYGB/L and phosphoglucomutase 1 (PGM1) being associated with worse overall survival. The importance of metabolic buffering in suppressing phenotypic transitions likely extrapolates to other cancer types. HighlightsO_LIMelanoma phenotypes are distinguished by their ability to store and mobilize glycogen. C_LIO_LIProliferative MITFHigh melanoma cells store glycogen to improve survival under stressful conditions. C_LIO_LIInhibition of glycogen degradation impairs proliferation in MITFHigh melanoma cells. C_LIO_LILack of PGM1 drives invasion and metastatic dissemination. C_LI

cancer biology↗

bioRxiv2024

Functional specialization of MITF, TFEB and TFE3 drives radically distinct adaptive gene expression programs in melanoma.

Cells can contain multiple related transcription factors targeting the same sequences, leading to potential regulatory cooperativity, redundancy, competition or temporally regulated factor exchange. Yet the differential biological functions of co-targeting transcription factors are poorly understood. In melanoma, three highly related transcription factors are co-expressed: The mTORC1-regulated TFEB and TFE3, key effectors of a wide range of metabolic and microenvironmental cues assumed to perform similar functions; and MITF, that controls melanoma phenotypic identity. Here we reveal the functional specialization of MITF, TFE3 and TFEB and their impact on melanoma progression. Notably, although all bind the same sequences, each regulates different and frequently opposing gene expression programs to coordinate differentiation, metabolism, and protein synthesis, and qualitatively and quantitatively impact tumor immune infiltration. The results uncover a hierarchical cascade whereby microenvironmental stresses, including glucose limitation, lead MITF, TFEB and TFE3 to drive distinct biologically important transcription programs that underpin phenotypic transitions in cancer.

cancer biology↗

bioRxiv2024

SIRT1 mediates the antagonism of Wnt/β-catenin pathway by vitamin D in colon carcinoma cells.

Cancer initiation and progression result from both genetic alterations and epigenetic reprograming caused by environmental or endogenous factors which can lead to aberrant cell signalling. Most colorectal cancers (CRC) are linked to the abnormal activation of the Wnt/ {beta}-catenin pathway, whose key feature is the accumulation of acetylated {beta}-catenin protein within the nucleus of colon epithelial cells. Nuclear {beta}- catenin acts as a transcriptional co-activator that alters the expression of many target genes involved in cell proliferation and invasion. The most active vitamin D metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol) can antagonize the over-activated Wnt/ {beta}-catenin pathway via binding to its high affinity receptor VDR. Here, we show that the activation of the SIRT1 deacetylase by 1,25(OH)2D3-bound VDR promotes deacetylation and nuclear exclusion of {beta}-catenin and, consequently, the downregulation of its pro-tumorigenic target genes and the inhibition of human colon carcinoma cell proliferation. Notably, orthogonal SIRT1 activation systematically drives nuclear exclusion of {beta}-catenin, highlighting the key role of SIRT1 in CRC. Since nuclear localization of {beta}-catenin is a critical driver of CRC initiation and progression that requires its acetylation, our results provide a mechanistic basis for the epidemiological evidence linking vitamin D deficiency and increased CRC risk and mortality.

cancer biology↗

bioRxiv2024

Phenotype-specific melanoma uptake of fatty acid from human adipocytes activates AXL and CAV1-dependent beta-catenin nuclear accumulation

Phenotypic diversity of cancer cells within tumors generated through bi-directional interactions with the tumor microenvironment has emerged as a major driver of disease progression and therapy resistance. Nutrient availability plays a critical role in determining phenotype, but whether specific nutrients elicit different responses on distinct phenotypes is poorly understood. Here we show, using melanoma as a model, that only MITFLow undifferentiated cells, but not MITFHigh cells, are competent to drive lipolysis in human adipocytes. In contrast to MITFHigh melanomas, adipocyte-derived free fatty acids are taken up by undifferentiated MITFLow cells via a fatty acid transporter (FATP)-independent mechanism. Importantly, oleic acid (OA), a monounsaturated long chain fatty acid abundant in adipose tissue and lymph, reprograms MITFLow undifferentiated melanoma cells to a highly invasive state by ligand-independent activation of AXL, a receptor tyrosine kinase associated with therapy resistance in a wide range of cancers. AXL activation by OA then drives SRC-dependent formation and nuclear translocation of a {beta}-catenin-CAV1 complex. The results highlight how a specific nutritional input drives phenotype-specific activation of a pro-metastasis program with implications for FATP-targeted therapies.

cancer biology↗

bioRxiv2023

Vitamin D induces SIRT1 activation through K610 deacetylation in colon cancer

Posttranslational modifications of epigenetic modifiers provide a flexible and timely mechanism for rapid adaptations to the dynamic environment of cancer cells. SIRT1 is an NAD+-dependent epigenetic modifier whose activity is classically associated with healthy aging and longevity, but its function in cancer is not well understood. Here, we reveal that 1,25-dihydroxyvitamin D3 (1,25(OH)2D3, calcitriol), the active metabolite of vitamin D (VD), promotes SIRT1 activation through auto-deacetylation in human colon carcinoma cells, and identify lysine 610 as an essential driver of SIRT1 activity. Remarkably, our data show that the post-translational control of SIRT1 activity mediates the antiproliferative action of 1,25(OH)2D3. This effect is reproduced by the SIRT1 activator SRT1720, suggesting that SIRT1 activators may offer new therapeutic possibilities for colon cancer patients who are VD deficient or unresponsive. Moreover, this might be extrapolated to inflammation and other VD deficiency-associated and highly prevalent diseases in which SIRT1 plays a prominent role.

cancer biology↗