Biology subjects

Oliveira, E.

Publications and source records attributed to Oliveira, E..

3 recordsLinked to original sources

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↗

bioRxiv2023

Epigenetic heritability of cell plasticity drives cancer drug resistance through one-to-many genotype to phenotype mapping

Cancer drug resistance is multi-factorial, driven by heritable (epi)genetic changes but also phenotypic plasticity. Here we dissect it by perturbing colorectal cancer patient-derived organoids longitudinally with drugs in sequence. Combining longitudinal tracking, single cell omics, evolutionary modelling, and machine leaning, we found that different targeted drugs select for distinct subclones, supporting rationally designed drug sequences. The cellular memory was encoded as a heritable epigenetic configuration, from which multiple transcriptional programmes could run, supporting a one-to-many (epi)genotype-to- phenotype map that explains how clonal expansions and plasticity manifest together. This may ensure drug resistance subclones can exhibit distinct phenotypes in changing environments while still preserving the cellular memory encoding for their selective advantage. Chemotherapies resistance was instead entirely driven by plasticity. Inducing further chromosomal instability before drug application changed clonal evolution but not convergent transcriptional programmes. Collectively, our data show how genetic and epigenetic alterations are selected to "permissive epigenome" enabling phenotypic plasticity.

cancer biology↗

bioRxiv2023

Therapeutic Targeting of TIM-4-L With Engineered T Cells for Acute Myeloid Leukemia

Disruption of the lipid asymmetric bilayer is a common feature observed in cancer cells. We utilized the natural immune receptor TIM-4 to interrogate for loss of plasma membrane phospholipid polarity in primary acute myelogenous leukemia (AML) samples. We performed FACs analysis in 33 patients and correlated TIM-4-L expression frequency and intensity with molecular disease characteristics. In normal tissues, TIM-4-L is confined to the internal leaflet of the plasma membrane. By contrast, 86% of untreated AML blasts in our analysis displayed upregulation of cell surface TIM-4-L. These observations were agnostic to AML genetic classification, as samples with mutations in TP53, ASXL1, and RUNX1, also displayed TIM-4-L upregulation similar to that seen in favorable and intermediate subtypes. This TIM-4-L dysregulation was also stably present in both Kasumi-1 and MV-4-11 AML cell lines. To evaluate the potential of upregulated TIM-4-L to serve as a target for adoptive T cell therapy (ACT), we constructed TIM-4-L-directed engineered T cells, which demonstrated potent anti-leukemic effects, effectively eliminating AML cell lines both in vitro and in vivo. This approach led to the eradication of AML cells across a range of endogenous TIM-4-L expression levels. These results highlight TIM-4-L as a highly prevalent and novel target for T cell-based therapy in AML. Further investigations into the role of TIM-4-L in AML pathogenesis and its potential as an anti-leukemic target for clinical development are warranted.

cancer biology↗