Colon tumour cell death causes mTOR dependence by paracrine P2X4 stimulation

Schmitt, Mark R.; Ceteci, Fatih; Gupta, J. R. P.; Pešić, Marina; Böttger, Tim W; Nicolas, Adele M.; Kennel, Kilian B; Engel, Esther; Schewe, Matthias; Kirisözü, Asude Callak; Petrocelli, Valentina; Dabiri, Yasamin; Varga, Júlia; Ramakrishnan, Mallika; Karimova, Madina; Ablasser, Andrea; Sato, Toshiro; Arkan, Melek C.; Sauvage, Frédéric J. de; Greten, Florian R.

doi:10.1038/s41586-022-05426-1

Cited by 43 publications

(29 citation statements)

References 39 publications

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“…mTORC1 is a multiprotein complex composed of mTOR, mLST8, and Raptor, sensitive to rapamycin inhibition [ 11 ]. mTORC1 is a central integrator of several cues (nutrient sensing, growth factor signaling, stress signaling pathways) to regulate cell growth and survival, proliferation, and the balance between most anabolic processes, including protein synthesis and autophagy [ 12 , 13 ].…”

Section: Autophagymentioning

confidence: 99%

Nanomedicine for autophagy modulation in cancer therapy: a clinical perspective

et al. 2023

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In recent years, progress in nanotechnology provided new tools to treat cancer more effectively. Advances in biomaterials tailored for drug delivery have the potential to overcome the limited selectivity and side effects frequently associated with traditional therapeutic agents. While autophagy is pivotal in determining cell fate and adaptation to different challenges, and despite the fact that it is frequently dysregulated in cancer, antitumor therapeutic strategies leveraging on or targeting this process are scarce. This is due to many reasons, including the very contextual effects of autophagy in cancer, low bioavailability and non-targeted delivery of existing autophagy modulatory compounds. Conjugating the versatile characteristics of nanoparticles with autophagy modulators may render these drugs safer and more effective for cancer treatment. Here, we review current standing questions on the biology of autophagy in tumor progression, and precursory studies and the state-of-the-art in harnessing nanomaterials science to enhance the specificity and therapeutic potential of autophagy modulators.

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Section: Autophagymentioning

confidence: 99%

Nanomedicine for autophagy modulation in cancer therapy: a clinical perspective

et al. 2023

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“…Recently, a crosstalk between colorectal cancer and non-transformed intestinal stem cells was shown to be mediated by clonal competition and super-competitor Apc -dependent Notum signalling, that induces the death of the naïve stem cells. This impact of the cancer cell on non-transformed neighbouring naive intestinal stem cells was shown to be crucial for tumour development (Flanagan et al, 2021a; Schmitt et al, 2022) (van Neerven et al, 2021). Given the strong impact on WNT signalling and the extended control of β-Catenin by USP10, we examined whether Usp10 is required for the super-competitor phenotype and, specifically, if silencing of USP10 could oppose this signalling axis.…”

Section: Resultsmentioning

confidence: 99%

“…Not only does USP10 control tumour intrinsic pathways and biological processes regulated by WNT, loss of USP10 suppressed cell death of non-transformed cells exposed to cultured medium from tumour organoids. Given that the super competitor signalling cascade (Flanagan et al, 2021b; Schmitt et al, 2022; van Neerven et al, 2021) leads to the secretion of signalling molecules initiating cell death, loss of USP10 controls extrinsic signalling mechanisms and thereby opposes tumour growth. It is worth noting that the catalytic activity of USP10 was required for the effects observed; overexpression of the catalytic inactive form had no effect on global β-Catenin abundance nor on proliferation.…”

Section: Discussionmentioning

confidence: 99%

Stabilisation of β-Catenin-WNT signalling by USP10 in APC-truncatedcolorectal cancer drives cancer stemness and enables super-competitor signalling

Reissland

Hartmann

Tauch

et al. 2023

Preprint

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The contribution of deubiquitylating enzymes to β-Catenin stabilisation in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, we report the deubiquitylase USP10 as APC-truncation- specific regulator enhancer of β-Catenin stability, potentiating WNT signalling pathway in CRC and cancer stem cells. Mechanistically, interaction studies in various CRC cell lines and in vitro binding studies, together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via its USP10 unstructured N-terminus and requires truncated in the absence of full-length APC. Notably, loss of USP10 in CRISPR engineered intestinal organoids reduces tumorigenic properties of CRC cells and organoids, and blocks the super competitor-properties of APC-mutated intestinal cells, elicits induces the expression of differentiation genes, and opposes the APC-truncated phenotype in an intestinal hyperplasia model of D.melanogaster. Taken together, our findings reveal USP10s role in intestinal tumourigenesis by stabilising β-Catenin, leading to aberrant WNT signalling, enhancing cancer cell stemness and implicate the DUB USP10 as a cancer specific therapeutic vulnerability in Apc truncated CRC.

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“…Recently, 3D bioprint tumor models or organoid models have become very suitable for exploring precision chemotherapy 44 . In patient‐derived tumour organoids from human colorectal cancer, the researcher found that chemotherapy‐induced tumour cell death causes ATP release triggering P2X4 to promote live cancer cell survival in a mammalian target of rapamycin‐dependent manner 45 . Maybe, we can use Abs against AREG or bFGF to abrogate the NF‐KB signalling triggered by chemotherapy or radiotherapy in tongue cancer organoid model in the future.…”

Section: Discussionmentioning

confidence: 99%

“… 44 In patient‐derived tumour organoids from human colorectal cancer, the researcher found that chemotherapy‐induced tumour cell death causes ATP release triggering P2X4 to promote live cancer cell survival in a mammalian target of rapamycin‐dependent manner. 45 Maybe, we can use Abs against AREG or bFGF to abrogate the NF‐KB signalling triggered by chemotherapy or radiotherapy in tongue cancer organoid model in the future. Of course, the roles and mechanisms of AREG and bFGF in tumour cell repopulation and recurrence in cancer need further investigation.…”

Section: Discussionmentioning

confidence: 99%

XBP1‐elicited environment by chemotherapy potentiates repopulation of tongue cancer cells by enhancing miR‐22/lncRNA/KAT6B‐dependent NF‐κB signalling

Jia

Wang

et al. 2023

Clinical & Translational Med

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Background: Tumour repopulation initiated by residual tumour cells in response to cytotoxic therapy has been described clinically and biologically, but the mechanisms are unclear. Here, we aimed to investigate the mechanisms for the tumour-promoting effect in dying cells and for tumour repopulation in surviving tongue cancer cells.Methods: Tumour repopulation in vitro and in vivo was represented by luciferase activities. The differentially expressed cytokines in the conditioned medium (CM) were identified using a cytokine array. Gain or loss of function was investigated using inhibitors, neutralising antibodies, shRNAs and ectopic overexpression strategies. Results: We found that dying tumour cells undergoing cytotoxic therapy increase the growth of living tongue cancer cells in vitro and in vivo. Dying tumour cells create amphiregulin (AREG)-and basic fibroblast growth factor (bFGF)-based extracellular environments via cytotoxic treatment-induced endoplasmic reticulum stress. This environment stimulates growth by activating lysine acetyltransferase 6B (KAT6B)-dependent nuclear factor-kappa B (NF-κB) signalling in living tumour cells. As direct targets of NF-κB, miR-22 targets KAT6B to repress its expression, but long noncoding RNAs (lncRNAs) Xiaoting Jia, Ge Wang and Lihong Wu contributed equally to the work.

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Colon tumour cell death causes mTOR dependence by paracrine P2X4 stimulation

Cited by 43 publications

References 39 publications

Nanomedicine for autophagy modulation in cancer therapy: a clinical perspective

Nanomedicine for autophagy modulation in cancer therapy: a clinical perspective

Stabilisation of β-Catenin-WNT signalling by USP10 in APC-truncatedcolorectal cancer drives cancer stemness and enables super-competitor signalling

XBP1‐elicited environment by chemotherapy potentiates repopulation of tongue cancer cells by enhancing miR‐22/lncRNA/KAT6B‐dependent NF‐κB signalling

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