bims-ectoca 2024-03-03 papers

Issue of 2024‒03‒03
four papers selected by
Ankita Daiya, BITS Pilani

Trends Cancer. 2024 Feb 29. pii: S2405-8033(24)00028-1. [Epub ahead of print]

Persisting cancer cells are different from bacterial persisters.

The persistence of drug-sensitive tumors poses a significant challenge in cancer treatment. The concept of bacterial persisters, which are a subpopulation of bacteria that survive lethal antibiotic doses, is frequently used to compare to residual disease in cancer. Here, we explore drug tolerance of cancer cells and bacteria. We highlight the fact that bacteria, in contrast to cancer cells, have been selected for survival at the population level and may therefore possess contingency mechanisms that cancer cells lack. The precise mechanisms of drug-tolerant cancer cells and bacterial persisters are still being investigated. Undoubtedly, by understanding common features as well as differences, we, in the cancer field, can learn from microbiology to find strategies to eradicate persisting cancer cells.

Keywords: bacterial persisters; drug resistance; drug tolerance; epigenetics; quiescence; residual disease in cancer

DOI: https://doi.org/10.1016/j.trecan.2024.02.002

Transl Oncol. 2024 Feb 26. pii: S1936-5233(23)00234-6. [Epub ahead of print]43 101848

Loss of p53 epigenetically modulates epithelial to mesenchymal transition in colorectal cancer.

Shreya Sharma, Harsha Rani, Yeshwanth Mahesh, Mohit Kumar Jolly, Jagannath Dixit, Vijayalakshmi Mahadevan.

Epithelial to Mesenchymal transition (EMT) drives cancer metastasis and is governed by genetic and epigenetic alterations at multiple levels of regulation. It is well established that loss/mutation of p53 confers oncogenic function to cancer cells and promotes metastasis. Though transcription factors like ZEB1, SLUG, SNAIL and TWIST have been implied in EMT signalling, p53 mediated alterations in the epigenetic machinery accompanying EMT are not clearly understood. This work attempts to explore epigenetic signalling during EMT in colorectal cancer (CRC) cells with varying status of p53. Towards this, we have induced EMT using TGFβ on CRC cell lines with wild type, null and mutant p53 and have assayed epigenetic alterations after EMT induction. Transcriptomic profiling of the four CRC cell lines revealed that the loss of p53 confers more mesenchymal phenotype with EMT induction than its mutant counterparts. This was also accompanied by upregulation of epigenetic writer and eraser machinery suggesting an epigenetic signalling cascade triggered by TGFβ signalling in CRC. Significant agonist and antagonistic relationships observed between EMT factor SNAI1 and SNAI2 with epigenetic enzymes KDM6A/6B and the chromatin organiser SATB1 in p53 null CRC cells suggest a crosstalk between epigenetic and EMT factors. The observed epigenetic regulation of EMT factor SNAI1 correlates with poor clinical outcomes in 270 colorectal cancer patients taken from TCGA-COAD. This unique p53 dependent interplay between epigenetic enzymes and EMT factors in CRC cells may be exploited for development of synergistic therapies for CRC patients presenting to the clinic with loss of p53.

Keywords: Cancer epigenetics; Epithelial to mesenchymal transition; SATB1; colorectal cancer; p53

DOI: https://doi.org/10.1016/j.tranon.2023.101848

Cell Death Dis. 2024 Feb 28. 15(2): 176

mTOR pathway occupies a central role in the emergence of latent cancer cells.

Kseniia V Aleksandrova, Mikhail L Vorobev, Irina I Suvorova.

The current focus in oncology research is the translational control of cancer cells as a major mechanism of cellular plasticity. Recent evidence has prompted a reevaluation of the role of the mTOR pathway in cancer development leading to new conclusions. The mechanistic mTOR inhibition is well known to be a tool for generating quiescent stem cells and cancer cells. In response to mTOR suppression, quiescent cancer cells dynamically change their proteome, triggering alternative non-canonical translation mechanisms. The shift to selective translation may have clinical relevance, since quiescent tumor cells can acquire new phenotypical features. This review provides new insights into the patterns of mTOR functioning in quiescent cancer cells, enhancing our current understanding of the biology of latent metastasis.

DOI: https://doi.org/10.1038/s41419-024-06547-3

Cytoskeleton (Hoboken). 2024 Mar 01.

The ability of the LIMD1 and TRIP6 LIM domains to bind strained f-actin is critical for their tension dependent localization to adherens junctions and association with the Hippo pathway kinase LATS1.

Samriddha Ray, Chamika DeSilva, Ishani Dasgupta, Sebastian Mana-Capelli, Natasha Cruz-Calderon, Dannel McCollum.

A key step in regulation of Hippo pathway signaling in response to mechanical tension is recruitment of the LIM domain proteins TRIP6 and LIMD1 to adherens junctions. Mechanical tension also triggers TRIP6 and LIMD1 to bind and inhibit the Hippo pathway kinase LATS1. How TRIP6 and LIMD1 are recruited to adherens junctions in response to tension is not clear, but previous studies suggested that they could be regulated by the known mechanosensory proteins α-catenin and vinculin at adherens junctions. We found that the three LIM domains of TRIP6 and LIMD1 are necessary and sufficient for tension-dependent localization to adherens junctions. The LIM domains of TRIP6, LIMD1, and certain other LIM domain proteins have been shown to bind to actin networks under strain/tension. Consistent with this, we show that TRIP6 and LIMD1 colocalize with the ends of actin fibers at adherens junctions. Point mutations in a key conserved residue in each LIM domain that are predicted to impair binding to f-actin under strain inhibits TRIP6 and LIMD1 localization to adherens junctions and their ability to bind to and recruit LATS1 to adherens junctions. Together these results show that the ability of TRIP6 and LIMD1 to bind to strained actin underlies their ability to localize to adherens junctions and regulate LATS1 in response to mechanical tension.

Keywords: Hippo signaling; LIM domain proteins; adherens junctions; f-actin; mechanical stress

DOI: https://doi.org/10.1002/cm.21847