Biology subjects

Piskounova, E.

Publications and source records attributed to Piskounova, E..

6 recordsLinked to original sources

bioRxiv2026

Sustained interferon exposure creates a hyper-metastatic subset of melanoma cells

We generated interferon signaling reporters in human and mouse melanoma cells and observed heterogeneity in interferon responses among cells in the same tumors. This was marked by inflamed regions within primary tumors that contained increased numbers of interferon-expressing macrophages/monocytes and elevated type I interferon signaling in melanoma cells. Melanoma cells that expressed GFP-Interferon stimulated gene 15 (ISG15) or GFP-Interferon-induced protein with tetraticopeptide repeats 3 (IFIT3) fusion reporters exhibited a profoundly increased ability to form metastatic tumors as compared to GFP-ISG15- melanoma cells from the same tumors, particularly when transplanted into immunocompetent mice. The increased metastatic potential of GFP-ISG15+ cells was driven partly by increased CD47 expression, which protected metastasizing cells from phagocytosis by macrophages. Macrophages are thus a double-edged sword, inhibiting the development of metastatic disease by phagocytosing disseminated melanoma cells, but promoting the emergence of a hyper-metastatic subpopulation of cells in inflamed regions of primary tumors as a consequence of sustained interferon production. One sentence summarySustained interferon exposure within inflamed regions of primary tumors dramatically increases the metastatic potential of a subpopulation of melanoma cells, partly by promoting CD47 expression, which protects against phagocytosis by macrophages.

cancer biology↗

bioRxiv2025

tRNA modifications are required for stress granule formation and melanoma metastasis

Metastasis is the leading cause of cancer related deaths, however therapies specifically targeting metastasis are lacking and remain a dire therapeutic need in the clinic. Metastasis is a highly inefficient process that is inhibited by extracellular stress. Therefore, metastasizing cells that ultimately survive and successfully colonize distant organs must undergo molecular rewiring to mitigate stress. Wobble uridine modifications, especially 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U34), have been implicated in stress response and poor prognosis of cancer patients. We use a patient derived xenograft (PDX) model of melanoma metastasis to study the role of the mcm5s2U34 modification in the stress response of metastasizing cells. We find that upon depletion of elongator acetyltransferase complex subunit 1 (ELP1)-- a component of the mcm5s2U34 pathway on [Formula], and [Formula] --codon-biased translation, migration, invasion, and metastatic burden in vivo is reduced. Further, we observe that stress granule components are enriched in a subset of codon-biased genes that are exclusively upregulated at the protein level in metastatic nodules compared to the primary tumor in our PDX model. Additionally, upon knockdown of ELP1, stress granule components have decreased protein expression with no significant change to their mRNA levels. Efficient translation, mediated by the carboxy-methylation arm of the mcm5s2U34 modification, is required for metastasizing cancer cells to withstand stress via stress granule formation and increase survival throughout the metastatic cascade. This makes the mcm5s2U34 machinery a potentially actionable therapeutic target, specific to metastatic disease.

cancer biology↗

bioRxiv2023

Selenocysteine tRNA methylation promotes oxidative stress resistance in melanoma metastasis

Selenocysteine-containing proteins play a central role in redox homeostasis. Their translation is a highly regulated process, dependent upon two tRNASec isodecoders differing by a single 2-O-ribose methylation, called Um34. We characterized FTSJ1 as the Um34 methyltransferase and show that its activity is required for efficient selenocysteine insertion at the UGA stop codon during translation. Specifically, Loss of Um34 leads to ribosomal stalling and decreased UGA recoding. FTSJ1-deficient cells are more sensitive to oxidative stress and have decreased metastatic colonization in xenograft models of melanoma metastasis. We found that FTSJ1 mediates efficient translation of selenoproteins essential for the cellular antioxidant response. Our findings uncover a role for tRNASec Um34 modification in oxidative stress resistance and highlight FTSJ1 as a potential therapeutic target specific for metastatic disease.

cancer biology↗

bioRxiv2023

NADK Isoform 3 promotes oxidative stress resistance and melanoma metastasis

Metastasizing cancer cells encounter a multitude of stresses throughout the metastatic cascade. Oxidative stress is known to be a major barrier for metastatic colonization, such that metastasizing cancer cells must rewire their metabolic pathways to increase their antioxidant capacity. NADPH is essential for regeneration of cellular antioxidants and several NADPH-regenerating pathways have been shown to play a role in metastasis. We have found that metastatic melanoma cells have increased levels of both NADPH and NADP+ suggesting increased de novo biosynthesis of NADP+. De novo biosynthesis of NADP+ occurs through a single enzymatic reaction catalyzed by NAD+ kinase (NADK). Here we show that different NADK isoforms are differentially expressed in metastatic melanoma cells, with Isoform 3 being specifically upregulated in metastasis. We find that Isoform 3 is more potent in expanding the NADP(H) pools, increasing oxidative stress resistance and promoting metastatic colonization compared to Isoform 1. We have found that Isoform 3 is transcriptionally upregulated by oxidative stress through the action of NRF2. Together, our work presents a previously uncharacterized role of NADK isoforms in oxidative stress resistance and metastasis and suggests that NADK Isoform 3 is a potential therapeutic target in metastatic disease.

cancer biology↗

bioRxiv2021

A nuclear cAMP microdomain suppresses tumor growth by Hippo pathway inactivation

cAMP signaling pathways are critical for both oncogenesis and tumor suppression. cAMP signaling is localized to multiple spatially distinct microdomains, but the role of cAMP microdomains in cancer cell biology is poorly understood. We developed a tunable genetic system that allows us to activate cAMP signaling in specific microdomains. We uncovered a previously unappreciated nuclear cAMP microdomain that functionally activates a tumor suppressive pathway in a broad range of cancers by inhibiting YAP, a key effector protein of the Hippo pathway, inside the nucleus. We show that nuclear cAMP induces a LATS-dependent pathway leading to phosphorylation of nuclear YAP solely at serine 397, export of YAP from the nucleus, without YAP protein degradation. Thus, nuclear cAMP inhibition of nuclear YAP is distinct from other known mechanisms of Hippo regulation. Pharmacologic targeting of specific cAMP microdomains remains an untapped therapeutic approach for cancer, and since Hippo pathway deregulation can lead to oncogenesis and chemotherapeutic resistance, drugs directed at the nuclear cAMP microdomain may provide new avenues for the treatment of cancer.

cancer biology↗

bioRxiv2021

Cell-type specific requirement for pyruvate dehydrogenase in hematopoiesis and leukemia development.

Cancer cells have different metabolic requirements as compared to their corresponding normal tissues. This is thought to reflect metabolic reprogramming during transformation. An alternative possibility is that some metabolic requirements of cancer cells reflect a maintenance of the metabolism of the specific normal cell type from which cancer cells originate. Here, we investigate this hypothesis by comparing glucose use in normal hematopoiesis and in leukemia. T cell progenitors in the thymus were glucose avid and oxidized more glucose in the tricarboxylic acid (TCA) cycle through pyruvate dehydrogenase (PDH) as compared to hematopoietic stem cells (HSCs) or other hematopoietic cells. PDH deletion reduced the number of double positive (DP) T cell progenitors but had no effect on HSCs, myeloid progenitors and other hematopoietic cells we examined. PDH deletion blocked the development of T cell leukemia from Pten-deficient DP progenitors, but not the development of a myeloid neoplasm from Pten-deficient HSCs or myeloid progenitors. Therefore, the requirement of glucose oxidation for leukemia development is inherited from the normal cell of origin and occurs independently of the driver genetic lesion. PDH was not required in vivo to generate acetyl-CoA or maintain levels of TCA cycle metabolites but to prevent pyruvate accumulation and to maintain glutathione levels and redox homeostasis.

cancer biology↗