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Cancer Stem Cells and Tumor Microenvironment Group: Bruno Sainz, Laura Martin-Hijano, Sonia Alcalá, Juan Carlos López, Adrián Palencia, Laura Ruiz, Diego Navarro and Sandra Batres

BIOGRAPHY
Dr. Bruno Sainz, a virologist by training, earned his PhD in Microbiology and Immunology from Tulane University in New Orleans, LA (USA) in 2005. His early scientific career focused on viral infections, such as Herpes simplex virus type-1, Ebola Virus, and SARS-CoV. Specifically, his research focused on developing inhibitors of viral entry and understanding and exploiting the innate immune Interferon (IFN) response to combat viral infections (funded by a National Institutes of Health (NIH, USA) NRSA research award). As a postdoctoral fellow at the Scripps Research Institute (2005-2006), he developed a more physiologically relevant hepatocyte culture system to study Hepatitis C Virus (HCV) infection in vitro. The more differentiated hepatocyte system also permitted him, while at the University of Illinois in Chicago (2006-2011), to independently discover that the Niemann-Pick C1-Like 1 (NPC1L1) cholesterol absorption receptor is an HCV entry factor and the clinically-available and FDA-approved NPC1L1 antagonist ezetimibe (Zetia) can potently block HCV uptake in vitro and in mice with human liver grafts. These findings translated into a 2012 Nature Medicine publication, a US patent, invited talks and presentations at international conferences and institutes and several follow-up publications.
As a semi-independent investigator at the CNIO in Spain from 2011-2014, Dr. Sainz changed his research focus and began to study cancer stem cell (CSC) biology in pancreatic cancer. He identified several immune proteins that have powerful pro-CSC properties, including the human cationic antimicrobial protein 18 (hCAP-18)/LL-37 peptide and the Interferon-Stimulated Gene 15 protein (ISG15). The sum of these studies have advanced our understanding of CSC pathobiology. In addition to the contributions described above, his contributions to science and specifically to the CSC field are best exemplified by his numerous publications aimed at dissecting the biological and molecular signatures of CSCs. As an independent Ramón y Cajal investigator at the Universidad Autónoma de Madrid (UAM) from 2014-2020 and now as a Senior Scientist at the Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM, his laboratory, in collaboration with other groups, has discovered new CSCs biomarkers. One of these markers, known as autofluorescence, is the result of riboflavin accumulation in ABCG2-coated intracellular vesicles exclusively found in CSCs. Using this marker, and others discovered since (e.g., ANTXR1, CD47, etc), his laboratory has learned that CSCs are distinct from their non-CSC counterparts at the epigenetic level (e.g. genome methylation and miRNA profiles), and these differences in methylation and miRNA expression are necessary for the maintenance of these cells. In addition, his laboratory is studying the metabolic differences between CSCs and non-CSCs. While non-CSCs meet their energy requirements via glycolysis, CSCs depend on mitochondrial respiration (i.e. oxidative phosphorylation) to survive. Thus, mitochondrial respiration represents an Achille’s' heel of CSCs, and his group is exploiting new experimental compounds (IGN111) and targeting specific genes (e.g. ISG15) in order to alter CSC metabolic requirements.
Dr. Sainz is currently a Senior Scientist (Científico Titular) at the Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-UAM (since 2020), member of the IIBm Scientific Commission, the IRYCIS Research Commission and member of the IIBm Histology Committee. The accomplishments and research of the Sainz Lab have resulted in more than 95 publications, several awarded US (Cancer Research Institute, Concern Foundation), Spanish (ISCIII, AECC, ACANPAN, Beca FERO) and European (EURO-NanoMed) grants, 3 patent applications, numerous invited talks and presentations, editorial affiliations and international recognition. Dr. Sainz has a broad background in immunology, microbiology and oncology, with specific expertise in pancreatic cancer, small animal models of cancer and drug discovery.

ORCID

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RESEARCH INTERESTS
Cancer stem cells (CSCs), also known as tumor-initiating cells or tumor-propagating cells, constitute a biologically unique subset of stem-like cells within the bulk tumor cell population. These cells are believed to be important in metastasis and chemoresistance, and they are hypothesized to be key drivers of the multistep process of oncogenesis, giving rise to the clonogenic core of tumor tissues. In the Sainz laboratory, we study CSCs in the context of pancreatic ductal adenocarcinoma (PDAC), the 4th leading cause of cancer related deaths in developed countries. We are running a combined basic and translation research program, which synergistically combines studies on the biology of mouse and human CSCs, including their in vivo microenvironment, in order to enhance our understanding of the regulatory machinery of CSCs. Specifically, the avenues of research that the Sainz laboratory pursues, are:

1) The identification and characterization of new biomarkers for the detection of CSCs from different solid tumors. We (with collaborators) have recently discovered a new inherent biomarker present in CSCs across several solid tumors. This biomarker, known as autofluorescence, is the result of riboflavin accumulation in ABCG2-coated intracellular vesicles exclusively found in CSCs. We are currently using autofluorescence as a means of isolating CSCs for in depth biological and molecular characterization studies.

2) The identification of proteins that govern key CSC phenotypes, such as “stemness", epithelial to mesenchymal transition (EMT), oxidative phosphorylation (i.e. mitochondrial respiration) and chemoresistance. We have discovered that the Interferon Stimulated Gene 15 (ISG15) is not only up-regulated in CSCs, but its function as a Ubiquitin-like modifier is necessary for many CSCs biological processes, such as metabolic plasticity. In addition, we can enrich for CSCs by changing their carbon source (galactose versus glucose), allowing us to study key features such as immune evasion.

3) Comprehensively understand the cellular make-up of the CSC niche and the larger more complex tumor microenvironment, specifically the role of tumor-associated macrophages (TAMs) in "activating" CSCs, with respect to the different environmental proteins they can secrete (e.g., OSM) in response to cues from the tumor and how these proteins alter the function of the CSCs at the level of EMT and chemoresistance and the TME (e.g., LOXL2).

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RECENT PUBLICATIONS
The Sainz laboratory has recently published several important papers and reviews in the cancer stem cell and pancreatic cancer field (list of selected publications):

2023

1) Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma. Gut, 2023 Feb;72(2):345-359. PMID35428659

2022

2) Extensive preclinical validation of combined RMC-4550 and LY32114996 supports clinical investigation for KRAS mutant pancreatic cancer. Cell Reports Medicine, 2022 Nov;3(11):100815. PMID36384095

3) LAMC2 marks a tumor-initiating cell population with an aggresive signature in pancreatic cancer. Journal of Exp & Clin Cancer Research, 2022, 41(1):315. PMID36289544

2021

4) Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug. Journal of Exp & Clin Cancer Research, 2021, 40(1):382. PMID34857016

5) Bcl3 Couples Cancer Stem Cell Enrichment With Pancreatic Cancer Molecular Subtypes. Gastroenterology. 2021 Apr 2;S0016-5085(21)00578-3. PMID33819482

2020

6) Exploiting oxidative phosphorylation to promote the stem and immunoevasive properties of pancreatic cancer stem cells. Nature Communications. 2020 Oct 16;11(1):5265. PMID33067432

7) Targeting MAD2 modulates stemness and tumorigenesis in human Gastric Cancer cell lines. Theranostics. 2020 Jul 25;10(21):9601-9618. PMID32863948

8) Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells. Cancers. 2020 Jul 4;12(7):1790. PMID32635473

9) Loss of ISG15 expression and ISGylation Reduces Mitophagy and the Functionality and Metabolic Plasticity of Pancreatic Cancer Stem Cells. Nature Communications. 2020 May 29;11(1):2682. PMID32472071

10) Synergistic targeting and resistance to PARP inhibition in DNA damage repair-deficient pancreatic cancer. Gut. 2021 Apr;70(4):743-760. PMID32873698

2019

11) The Anthrax Toxin Receptor 1 (ANTXR1) Is Enriched in Pancreatic Cancer Stem Cells Derived from Primary Tumor Cultures. Stem Cells Int. 2019 May 2;2019:1378639. PMID31191663

12) Complete Regression of Advanced Pancreatic Ductal Adenocarcinomas upon Combined Inhibition of EGFR and C-RAF. Cancer Cell. 2019 Apr 15;35(4):573-587.e6. PMID30975481

13) Tumor-associated macrophage-secreted 14-3-3ζ signals via AXL to promote pancreatic cancer chemoresistance. Oncogene. 2019 Jul;38(27):5469-5485. PMID30936462

14) Levels of autophagy related 5 protein affect progression and metastasis of pancreatic tumors in mice. Gastroenterology. 2019 Jan;156(1):203-217.e20. PMID30296435

2018

15) Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nature Medicine. 2018 Jul 24(7):954-960. PMID29808009

16) The Ever-Evolving Concept of the Cancer Stem Cell in Pancreatic Cancer. Cancers. 2018 Jan 26;10(2). pii: E33. PMID29373514

17) Saa3 is a key mediator of the protumorigenic properties of cancer-associated fibroblasts in pancreatic tumors. Proc Natl Acad Sci USA (PNAS). 2018 Feb 6;115(6):E1147-E1156. PMID29351990

2017

18) A current perspective on cancer immune therapy: step-by-step approach to constructing the magic bullet. Clin Transl Med. 2017 Dec;6(1):3. PMID28050779

19) GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer. Gut. 2017 Sep;66(9):1665-1676. PMID27325420

2016

20) DNMT1 inhibition reprograms pancreatic cancer cells via upregulation of the miR-17-92cluster. Cancer Research. 2016 Aug 1;76(15):4546-58. PMID27261509

21) Cancer Stem Cells and Macrophages: Implications in Tumor Biology and Therapeutic Strategies. Mediators of Inflammation. 2016:9012369. PMID26980947

2015

22) MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells. Cell Metabolism. 2015 Oct 6;22(4):590-605. PMID26365176

23) The miR-17-92 cluster counteracts quiescence and chemoresistance in a distinct subpopulation of pancreatic cancer stem cells. Gut. 2015 Dec;64(12):1936-48. PMID25887381

24) Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment. Gut. 2015 Dec;64(12):1921-35. PMID25841238

2014

25) ISG15 is a critical microenvironmental factor for pancreatic cancer stem cells. Cancer Research. 2014 Dec 15;74(24):7309-20. PMID25368022

26) Intracellular autofluorescence: a biomarker for epithelial cancer stem cells. Nature Methods. 2014 Nov;11(11):1161-9. PMID25262208

FULL LIST OF PUBLICATIONS

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FUNDING
Our laboratory is currently funded by several national and international grants, including:

1) Project Title: Proyecto FIS (PI21/01110) - Utility of new pancreatic ductal adenocarcinoma subtype profiles for the discoery of druggable targets or pathways: new tools for personalized medicine. 
Funding Source: ISCII & Spanish Ministry of Science, Innovation & Universities

2) Project Title: “RuCSC” - targeting cancer stem cells using ruthenium compounds
Funding Source: Programa Ignicia prueba de concepto, an initiative of the Agencia Gallega de Innovación (GAIN) to facilitate the access of I+D+i projects to the market. This project, financed with 386.603 Euros is a collaborative project between la Universidad de Santiago de Compostela (USC) and la Universidad Autónoma de Madrid (UAM). More Information

3) Project Title: Combating Pancreatic Cancer by Identifying Those Genes Essential for Cancer Stem Cell-Mediated Tumorigenicity
Funding Source: Fundación Fero - 2018 BECA FERO FELLOWSHIP

4) Project Title: Photoactivable nanoparticles to immunostimulate the tumour microenvironment in pancreatic cancer (PANIPAC)
Funding Source: EURONANOMED III - JOINT TRANSNATIONAL CALL FOR PROPOSALS (2018)

5) Project Title: Proyecto FIS (PI18/00757) - The basal subtype of pancreatic cancer as a new tool towards personalized medicine: cellular and molecular characterization for the development of new therapies
Funding Source: ISCII & Spanish Ministry of Science, Innovation & Universities

6) Project Title: Identification of pancreatic cancer immune escape receptors.
Funding Source: Asociación Cáncer de Páncreas (ACANPAN)

7) Project Title: A multi-faceted approach to treating pancreatic cancer.
Funding Source: Asociación Española Contra el Cáncer (AECC), Grupos Coordinados Estables 2016: CNIO (Dr. Mariano Barbacid), IRyCIS (Dr. Alfredo Carrato) and UAM (Dr. Bruno Sainz)

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LINKS
We collaborate in several European initiatives and are part of the national Spanish network of health research centers:

PANIPAC

Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS)

CIBEROnc

PDAC-AECC