Endogenous and Exogenous Regulatory Signaling in the Secretory Pathway: Role of Golgi Signaling Molecules in Cancer

Giudice, Simona Del; Luca, Valentina De; Parizadeh, Seyedehnegar; Russo, Domenico; Luini, Alberto; Martino, Rosaria Di

doi:10.3389/fcell.2022.833663

Cited by 8 publications

(7 citation statements)

References 154 publications

(172 reference statements)

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“…Second, Rab1A and Rab1B were implicated in multiple human diseases that range from cancer to neurodegeneration ( Winslow et al, 2010 ; Coune et al, 2011 ; Thomas et al, 2014 ; Xu et al, 2015 ; Halberg et al, 2016 ). The two processes they regulate were also shown to be important for cancer ( Yun & Lee, 2018 ; Del Giudice et al, 2022 ) and neurological disorders ( Nah et al, 2015 ; Kuo et al, 2021 ). Data presented here enable teasing apart the association of Rab1A or Rab1B with these diseases (see below).…”

Section: Discussionmentioning

confidence: 99%

Dual function of Rab1A in secretion and autophagy: hypervariable domain dependence

et al. 2023

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We currently understand how the different intracellular pathways, secretion, endocytosis, and autophagy are regulated by small GTPases. In contrast, it is unclear how these pathways are coordinated to ensure efficient cellular response to stress. Rab GTPases localize to specific organelles through their hypervariable domain (HVD) to regulate discrete steps of individual pathways. Here, we explored the dual role of Rab1A/B (92% identity) in secretion and autophagy. We show that although either Rab1A or Rab1B is required for secretion, Rab1A, but not Rab1B, localizes to autophagosomes and is required early in stress-induced autophagy. Moreover, replacing the HVD of Rab1B with that of Rab1A enables Rab1B to localize to autophagosomes and regulate autophagy. Therefore, Rab1A-HVD is required for the dual functionality of a single Rab in two different pathways: secretion and autophagy. In addition to this mechanistic insight, these findings are relevant to human health because both the pathways and Rab1A/B were implicated in diseases ranging from cancer to neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Dual function of Rab1A in secretion and autophagy: hypervariable domain dependence

et al. 2023

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“…Interestingly, several gene sets related to protein localization and ER-Golgi transport were also positively enriched. Though there is some evidence of a Golgi stress response and the upregulation of key Golgi-associated genes in cancer is implicated in metastasis and invasion, it remains unclear in the literature how Golgi function is impacted by microenvironmental conditions [45][46][47][48][49][50][51] . Such investigations have been hindered in part due to the lack of appropriate experimental models 45 ; therefore, this may be an interesting area for future investigation in TRACER, though beyond the scope of the current work.…”

Section: Expected and Novel Gradients In Gene Expression Are Observed...mentioning

confidence: 99%

Single-cell analysis of an engineered organoid-based model of pancreatic cancer identifies hypoxia as a contributing factor in the determination of transcriptional subtypes

Landon-Brace,

Innes,

Latour

et al. 2024

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is a high-mortality cancer characterized by its aggressive, treatment-resistant phenotype and a complex tumour microenvironment (TME) featuring significant hypoxia. Bulk transcriptomic analysis has identified the classical and basal-like transcriptional subtypes which have prognostic value in PDAC; however, it remains unclear how microenvironmental heterogeneity contributes to the expression of these transcriptional signatures. Here, we used single cell transcriptome analysis of the organoid TRACER platform to explore the effect of oxygen and other microenvironmental gradients on PDAC organoid cells. We found that the microenvironmental gradients present in TRACER significantly impact the distribution of organoid transcriptional phenotypes and the enrichment of gene sets linked to cancer progression and treatment resistance. More significantly, we found that microenvironmental gradients drive changes in the expression of the classical and basal-like transcriptional subtype gene signatures. This effect is likely dominated by the oxygen gradients in TRACER, as hypoxia alone induced decreases in the expression of classical marker GATA6 at both the gene and protein level in PDAC cells. This work suggests that hypoxia contributes to determining transcriptional subtypes in PDAC and broadly underscores the importance of considering microenvironmental gradients in organoid-based transcriptomic studies of PDAC.

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“…Several protein kinases play key roles in the secretory pathway at the trans-Golgi network and are generally hyperactivated in cancer cells, contributing to cancer progression [29]. Their inhibition has thus been studied as a GA trafficking disruption strategy with potential anticancer effects.…”

Section: Golgi Apparatus Trafficking Disrupting Agentsmentioning

confidence: 99%

The Golgi Apparatus as an Anticancer Therapeutic Target

Martins,

Vieira,

Pereira-Leite

et al. 2023

Biology

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Although the discovery of the Golgi apparatus (GA) was made over 125 years ago, only a very limited number of therapeutic approaches have been developed to target this complex organelle. The GA serves as a modification and transport center for proteins and lipids and also has more recently emerged as an important store for some ions. The dysregulation of GA functions is implicated in many cellular processes associated with cancer and some GA proteins are indeed described as cancer biomarkers. This dysregulation can affect protein modification, localization, and secretion, but also cellular metabolism, redox status, extracellular pH, and the extracellular matrix structure. Consequently, it can directly or indirectly affect cancer progression. For these reasons, the GA is an appealing anticancer pharmacological target. Despite this, no anticancer drug specifically targeting the GA has reached the clinic and few have entered the clinical trial stage. Advances in nanodelivery approaches may help change this scenario by specifically targeting tumor cells and/or the GA through passive, active, or physical strategies. This article aims to examine the currently available anticancer GA-targeted drugs and the nanodelivery strategies explored for their administration. The potential benefits and challenges of modulating and specifically targeting the GA function in the context of cancer therapy are discussed.

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Endogenous and Exogenous Regulatory Signaling in the Secretory Pathway: Role of Golgi Signaling Molecules in Cancer

Cited by 8 publications

References 154 publications

Dual function of Rab1A in secretion and autophagy: hypervariable domain dependence

Dual function of Rab1A in secretion and autophagy: hypervariable domain dependence

Single-cell analysis of an engineered organoid-based model of pancreatic cancer identifies hypoxia as a contributing factor in the determination of transcriptional subtypes

The Golgi Apparatus as an Anticancer Therapeutic Target

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