ΔNp63/p73 drive metastatic colonization by controlling a regenerative epithelial stem cell program in quasi-mesenchymal cancer stem cells

Lambert, Arthur W.; Fiore, Christopher; Chutake, Yogesh; Verhaar, Elisha R; Strasser, Patrick C; Chen, Mei Wei; Farouq, Daneyal; Das, Sunny; Li, Xin; Eaton, Elinor Ng; Zhang, Yun; Donaher, Joana Liu; Engstrom, Ian A.; Reinhardt, Ferenc; Yuan, Bingbing; Gupta, Sumeet; Wollison, Bruce M.; Eaton, Matthew L.; Bierie, Brian; Carulli, John P.; Olson, Eric R.; Guenther, Matthew G.; Weinberg, Robert A.

doi:10.1016/j.devcel.2022.11.015

Cited by 17 publications

(18 citation statements)

References 96 publications

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“…5j, Extended Data Fig. 4d ) , which, as we have found in other investigations, serve as a reliable marker of metastasis-initiating capacity 84 . In addition, we found that loss of ether lipids significantly attenuates the tumor-initiating potential and metastatic capacity of PyMT-1099 AGPS KO TGF-β-treated (ether lipid deficient) cancer cells following implantation into the orthotopic site –– the mammary stromal fat pad ( Fig.…”

Section: Resultssupporting

confidence: 61%

Ether lipids influence cancer cell fate by modulating iron uptake

Henry,

Müller,

Yang

et al. 2024

Preprint

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Cancer cell fate has been widely ascribed to mutational changes within protein-coding genes associated with tumor suppressors and oncogenes. In contrast, the mechanisms through which the biophysical properties of membrane lipids influence cancer cell survival, dedifferentiation and metastasis have received little scrutiny. Here, we report that cancer cells endowed with a high metastatic ability and cancer stem cell-like traits employ ether lipids to maintain low membrane tension and high membrane fluidity. Using genetic approaches and lipid reconstitution assays, we show that these ether lipid-regulated biophysical properties permit non-clathrin-mediated iron endocytosis via CD44, leading directly to significant increases in intracellular redox-active iron and enhanced ferroptosis susceptibility. Using a combination of in vitro three-dimensional microvascular network systems and in vivo animal models, we show that loss of ether lipids also strongly attenuates extravasation, metastatic burden and cancer stemness. These findings illuminate a mechanism whereby ether lipids in carcinoma cells serve as key regulators of malignant progression while conferring a unique vulnerability that can be exploited for therapeutic intervention.

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Section: Resultssupporting

confidence: 61%

Ether lipids influence cancer cell fate by modulating iron uptake

Henry,

Müller,

Yang

et al. 2024

Preprint

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“…Our data have implications for the control of EMT in squamous cells, and imply that TGFβ in the presence of variable levels of p63 will produce intermediate or partial EMT phenotypes (pEMT), the direction of which will vary depending on endogenous p63 levels and on time- and cell type-dependent effects of TGFβ. pEMT and epithelial mesenchymal plasticity (EMP) are increasingly recognized as playing important roles in tumor cell migration, metastasis, and therapeutic resistance 59 – 61 . In particular, graded pEMT in SCC cells produces substantial intratumor cell heterogeneity, and the extent of the pEMT phenotype within individual tumors is influenced by TGFβ to determine the likelihood of metastasis and patient prognosis 62 – 64 .…”

Section: Discussionmentioning

confidence: 99%

Complex and variable regulation of ΔNp63 and TAp63 by TGFβ has implications for the dynamics of squamous cell epithelial to mesenchymal transition

Pokorná,

Tylichová,

Vojtesek

et al. 2024

Sci Rep

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TGFβ has roles in inflammation, wound healing, epithelial to mesenchymal transition (EMT), and cancer stem cell states, and acts as a tumor suppressor gene for squamous cell carcinoma (SCC). SCCs are also characterized by high levels of ΔNp63, which induces epithelial cell phenotypes and maintains squamous stem cells. Previous studies indicate a complex interplay between ΔNp63 and TGFβ signaling, with contradictory effects reported. We investigated the effects of TGFβ on p63 isoform proteins and mRNAs in non-malignant squamous and SCC cells, and the role of either canonical or non-canonical TGFβ signaling pathways. TGFβ selectively increased ΔNp63 protein levels in non-malignant keratinocytes in association with SMAD3 activation and was prevented by TGFβ receptor inhibition, indicating activation of canonical TGFβ pathway signaling. TP63 isoform mRNAs showed discordance from protein levels, with an initial increase in both TAP63 and ΔNP63 mRNAs followed by a decrease at later times. These data demonstrate complex and heterogeneous effects of TGFβ in squamous cells that depend on the extent of canonical TGFβ pathway aberrations. The interplay between TGFβ and p63 is likely to influence the magnitude of EMT states in SCC, with clinical implications for tumor progression and response to therapy.

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“…While ‘teams’ comprising EMT-TFs and MET-TFs have been well established, it remains to be seen whether the molecular factors stabilizing hybrid E/M phenotypes such as NRF2 and Δ NP63 form a separate ‘team’ and how antagonistic they are with both EMT-TFs and MET-TFs ‘teams’ [80,81]. Moreover, although the role of RKIP and BACH1 in altering one of the axes of cancer cell plasticity at a time—EMT, stemness, ferroptosis, metabolic switching—has been well studied, their ability to drive adaptation along multiple axes simultaneously due to the impact of ‘teams’ remains to be investigated experimentally, to further lend credence to our model predictions.…”

Section: Discussionmentioning

confidence: 99%

A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity

Shyam,

Ramu,

Sehgal

et al. 2023

J. R. Soc. Interface.

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Epithelial–mesenchymal transition (EMT) is an important axis of phenotypic plasticity—a hallmark of cancer metastasis. Raf kinase-B inhibitor protein (RKIP) and BTB and CNC homology 1 (BACH1) are reported to influence EMT. In breast cancer, they act antagonistically, but the exact nature of their roles in mediating EMT and associated other axes of plasticity remains unclear. Here, analysing transcriptomic data, we reveal their antagonistic trends in a pan-cancer manner in terms of association with EMT, metabolic reprogramming and immune evasion via PD-L1. Next, we developed and simulated a mechanism-based gene regulatory network that captures how RKIP and BACH1 engage in feedback loops with drivers of EMT and stemness. We found that RKIP and BACH1 belong to two antagonistic ‘teams’ of players—while BACH1 belonged to the one driving pro-EMT, stem-like and therapy-resistant cell states, RKIP belonged to the one enabling pro-epithelial, less stem-like and therapy-sensitive phenotypes. Finally, we observed that low RKIP levels and upregulated BACH1 levels associated with worse clinical outcomes in many cancer types. Together, our systems-level analysis indicates that the emergent dynamics of underlying regulatory network enable the antagonistic patterns of RKIP and BACH1 with various axes of cancer cell plasticity, and with patient survival data.

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ΔNp63/p73 drive metastatic colonization by controlling a regenerative epithelial stem cell program in quasi-mesenchymal cancer stem cells

Cited by 17 publications

References 96 publications

Ether lipids influence cancer cell fate by modulating iron uptake

Ether lipids influence cancer cell fate by modulating iron uptake

Complex and variable regulation of ΔNp63 and TAp63 by TGFβ has implications for the dynamics of squamous cell epithelial to mesenchymal transition

A systems-level analysis of the mutually antagonistic roles of RKIP and BACH1 in dynamics of cancer cell plasticity

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