The protease‐inhibitor SerpinB3 as a critical modulator of the stem‐like subset in human cholangiocarcinoma

Correnti, Margherita; Cappon, A.; Pastore, Mirella; Piombanti, Benedetta; Lori, Giulia; Oliveira, Douglas Vnp; Munoz‐Garrido, Patricia; Lewińska, Monika; Andersen, Jesper B.; Coulouarn, Cédric; Sulpice, Laurent; Peraldo-Neia, Caterina; Cavalloni, Giuliana; Quarta, Santina; Biasiolo, Alessandra; Fassan, Matteo; Ramazzotti, Matteo; Parri, Matteo; Recalcati, Stefania; Tommaso, Luca Di; Campani, Claudia; Invernizzi, Pietro; Torzilli, Guido; Marra, Fabio; Pontisso, Patrizia; Raggi, Chiara

doi:10.1111/liv.15049

Cited by 22 publications

(31 citation statements)

References 47 publications

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“…There are several hypothesized mechanisms by which SerpinB3 could affect cancer-relevant phenotypes (e.g., impact on the stem cell state, resistance to apoptosis, invasion). A recent study in cholangiocarcinoma found that SerpinB3 was expressed in a stem-like subset of cells and that knockdown of SerpinB3 resulted in decreased invasion and proliferation (Correnti et al, 2021). In addition to its roles in cancer, SerpinB3 is Cell Reports 40, 111348, September 13, 2022 7 Article ll expressed in hepatic stem cells, where SerpinB3 expression correlates with decreased activated caspase 3 (Villano et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

SerpinB3 drives cancer stem cell survival in glioblastoma

Lauko¹,

Volovetz²,

Turaga³

et al. 2022

Cell Reports

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Section: Discussionmentioning

confidence: 99%

SerpinB3 drives cancer stem cell survival in glioblastoma

Lauko¹,

Volovetz²,

Turaga³

et al. 2022

Cell Reports

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“…The copyright holder for this preprint (which this version posted April 1, 2023. ; https://doi.org/10.1101/2023.03.29.534766 doi: bioRxiv preprint including hepatocellular carcinoma (34), cholangiocarcinoma (32), PDAC (36), glioblastoma (33), and breast cancer (35,45). In cancer, SERPINB3 has various functions including inhibition of radiation/anti-cancer drug-induced apoptosis, protein degradation, and intratumor infiltration of natural killer cells (27,34,46), and to promote metabolic reprogramming, angiogenesis, epithelial-mesenchymal transition, and secretion of inflammatory mediators (28,(32)(33)(34)(35)(36). SERPINB3 also upregulates MYC (30,31), which leads to the maintenance of cancer stemness (32,33).…”

Section: Discussionmentioning

confidence: 99%

“…Among them, SERPINB3 was ranked one of the top and robustly upregulated genes in the basal-like/progenitor subtype (Supplementary Table 2). SERPINB3 is also known as squamous cell carcinoma antigen (24)(25)(26)(27), associates with hypoxia (28,29), and promotes MYC activation (30,31), cancer stemness (32,33), metabolic reprogramming (28), and inflammation (34)(35)(36). These functions overlap the characteristics of basal-like/squamous subtype (3), and we chose SERPINB3 for further investigation.…”

Section: Serpinb3 Is Upregulated In Basal-like/squamous Subtype Of Pd...mentioning

confidence: 99%

SERPINB3 induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer

Ohara

Tang

Liu

et al. 2023

Preprint

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Pancreatic cancer is a heterogeneous disease with distinct subtypes. Here, we investigated candidate driver genes of the highly aggressive basal-like/squamous molecular subtype of pancreatic ductal adenocarcinoma (PDAC). Integrative transcriptomic analyses identified the upregulated serine/cysteine protease inhibitor, SERPINB3 (squamous cell carcinoma antigen 1, SCCA1) in basal-like/squamous PDAC using discovery and validation approaches. Upregulation of SERPINB3 associated with decreased patient survival and a transcriptome profile indicative of the basal-like/squamous subtype. In human PDAC cell lines, SERPINB3 transgene expression enhanced their invasion capability. Moreover, upregulated expression of SERPINB3 in AsPC-1 cells resulted in enhanced lung metastasis in an orthotopic xenograft model. Molecular analysis of the primary tumor xenografts indicated activation of pathways related to metastasis, increased oxidative damage, and angiogenesis when SERPINB3 was upregulated. Furthermore, metabolomic analysis, using patient cohorts and PDAC cell lines showed a distinct metabolic pattern closely associated with both SERPINB3 and the basal-like/squamous subtype, which included upregulation of carnitine/acylcarnitine, amino acid, glutathione, and purine metabolic pathways, and glycolysis. Further RNA-seq and metabolomic analyses indicated that SERPINB3 may potentially induce the basal-like/squamous subtype and metabolic reprogramming through MYC activation. Taken together, our findings identified SERPINB3 as a candidate marker gene for the basal-like/squamous subtype, which may contribute to the disease aggressiveness in this subtype of PDAC.

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“…There are several hypothesized mechanisms by which SerpinB3 could affect cancer-relevant phenotypes (impact on the stem cell state, resistance to apoptosis, invasion). A recent study in cholangiocarcinoma found that SerpinB3 was expressed in a stem-like subset of cells and that knockdown of SerpinB3 resulted in decreased invasion and proliferation (Correnti et al, 2021). In addition to its roles in cancer, SerpinB3 is expressed in hepatic stem cells, where SerpinB3 expression correlates with decreased activated caspase 3 (Villano et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

SerpinB3 drives cancer stem cell survival in glioblastoma

Lauko

Volovetz

Turaga

et al. 2021

Preprint

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Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC therapeutic resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. The knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. Mechanistically, SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced with radiation. Finally, we found that SerpinB3 knockdown dramatically increased the efficacy of radiation in pre-clinical models. Taken together, our findings identify a novel GBM CSC-specific survival mechanism involving a previously uninvestigated cysteine protease inhibitor, SerpinB3, and provide a potential target to improve the efficacy of standard-of-care GBM therapies against therapeutically resistant CSCs.

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The protease‐inhibitor SerpinB3 as a critical modulator of the stem‐like subset in human cholangiocarcinoma

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 22 publications

References 47 publications

SerpinB3 drives cancer stem cell survival in glioblastoma

SerpinB3 drives cancer stem cell survival in glioblastoma

SERPINB3 induces the basal-like/squamous subtype and enhances disease progression in pancreatic cancer

SerpinB3 drives cancer stem cell survival in glioblastoma

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