Laila Ritsma

Sr. Postdoctoral researcher / Hoofd van de Cell Signaling Dynamics group

Vakgebied(en)

  • Intravital microscopy
  • Breast cancer
  • Dormancy
  • Melanoma
  • Metastasis
  • TGF-beta signaling
  • Website: https://scholar.harvard.edu/lailaritsma

Introductie

Laila is a senior postdoc and head of the Cell Signaling Dynamics group at the LUMC, Dept. CCB. Her areas of interest include dormancy, intravital imaging, metastasis and microscopy. In April 2016 Laila started her own research line at the LUMC in Leiden in close collaboration with Peter ten Dijke. She uses intravital microscopy to study signaling dynamics during liver colonization and dormancy.

Laila is from the Netherlands, where she obtained her B.Sc. and M.Sc. in Bio-Medical Science. As part of these degrees she completed internships at the Dutch Cancer Institute (NKI), University Medical Center Utrecht (the Netherlands) and Peter MacCallum Cancer Center (Australia). She performed her PhD in the lab of Jacco van Rheenen at the Hubrecht Institute (the Netherlands) and studied the metastatic process using high-resolution intravital microscopy. During her graduate work she developed and optimized high-resolution intravital imaging technologies to study the metastatic process at the cellular level in living animals (Ritsma et al., Sci Transl Med, 2012; Ritsma et al., Nature Protocols, 2013; Ritsma et al., Nature Communications, 2013). Her work uncovered a highly migratory stage during liver metastasis colonization (Ritsma et al., Sci Transl Med, 2012) and provided new insights into intestinal stem cell homeostasis (Ritsma et al., Nature, 2014). She received an award from her graduate school (CS&D) in 2013 for the best publication of the past year, which was based on her Sci Transl Med paper in 2012. She graduated from Utrecht University in June 2013 and received the "ESMI Award for excellent PhD thesis" for her work performed in the van Rheenen lab.

In August 2013 she joined the Ramaswamy lab as a postdoctoral fellow. To perform her postdoctoral work she received the “rubicon” grant from the Dutch organization of Scientific Research (NWO) and a "postdoctoral fellowship" from the Susan G. Komen foundation, Tx, USA. Within the research laboratory of Sridhar Ramaswamy at Massachusetts General Hospital (MGH) she uncovered a new factor that increases Tumor Infiltrating Lymphocytes (TILs) in melanomas. She observed that activation of integrin beta1 leads to the release of active TGF-beta, which in turn increases TILs in a preclinical mouse model. This is associated with a long-term memory response and long-term survival. Moreover, these results were verified in patients using TCGA analyses (Ritsma et al, PlosOne, 2013).

Laila Ritsma's group now continues studying melanoma and breast cancer colonization of the liver using multiphoton intravital microscopy (See Research projects, below). 


Research projects

Research project 1: Awakening the sleeping beauty: towards a better understanding of cancer cell dormancy

Dr. Chloé Prunier

·       Breast cancer (BC) is the leading cancer diagnosed among women in the world (1). A large range of therapies is currently available, however, the inability to treat metastasis, one of the main source of cancer-related death, is now a major challenge faced by oncologists. Metastasis is linked to tumour cell dormancy(2,3), a state in which cells do not cycle and are resistant to chemotherapy(4). Between 36-56% of BC patients have dormant cells in their bone marrow(5) that can potentially relapse and form metastases at any time. This poses tumour cell dormancy as a major clinical problem. Several groups have implicated a role for the TGFβ signaling pathway in the regulation of dormancy and we have summarized the data in a review: Prunier et al, Trends in Cancer, 2019. DOI: 10.1016/j.trecan.2018.10.010

Now, we aim to better understand the molecular mechanisms that underlie single cell dormancy. To do so, we have thoroughly characterized a 3D in vitro dormancy assay (Barkan et al, Can Res, 2008) and investigated if this model shows overlap with senescence.  

Research project 2: Towards dynamic targeting of TGF-β in metastatic melanoma

Dieuwke Marvin, PhD Candidate; Daphne Makkinga, MSc Student

TGF-β inhibitors have produced mixed results in clinical trials with metastatic melanoma patients. Most metastatic melanoma patients diagnosed with liver metastases still die within months after diagnosis. Thus, treatments must be improved. To do so, we will increase our insights into how TGF-β signaling regulates hepatic colonization of metastatic melanoma cells. TGF-β regulates a variety of processes during metastasis including tumor cell intrinsic processes like cell migration and proliferation, but also tumor microenvironmental processes like activation of CAFs and the regulation of inflammation. Specific interplay between these processes most likely determines successful hepatic colonization of metastatic melanoma cells. We investigate the spatiotemporal patterns of TGF-β signaling in tumor and microenvironmental cells during melanoma metastasis using an improved fluorescent TGF-b transcriptional reporter system (Marvin et al, manuscript in prep) and unique advanced in vivo microscopy techniques. A detailed dissection of this process will likely guide us towards improved TGF-β blocking strategies by targeting specific cells and/or during specific colonization time windows. Ultimately, this will inform us on how to better use TGF-β inhibitors to treat melanoma liver metastases.


Publications

 H-Factor: 17. Average IPF: 9.144. Total citations: 1788. Average citation per item: 74.5

https://orcid.org/0000-0002-0214-2008

 1.       van den Berg CW, Koudijs A, Ritsma L*, Rabelink TJ*. In vivo assessment of size-selective glomerular sieving in transplanted human induced pluripotent stem cell-derived kidney organoids. 2020 J Am Soc Nephr IPF2018: 8.547

2.       Huis In 't Veld RV, Ritsma L, Kleinovink JW, Que I, Ossendorp F, Cruz LJ. Photodynamic cancer therapy enhances nanoparticles in tumor-associated myeloid cells. 2019 J Control Release. 320:19-31 IPF2018: 7.901

3.       Chen N, Ritsma LMA, Vrisekoop N. In vivo characteristics of human and mouse breast tumor cell lines. 2019 Experimental Cell Research. 381(1):86-93. IPF2018: 3.329

4.       Prunier C, Baker B, ten Dijke P, Ritsma L. TGF-b family signaling pathways in cellular dormancy. 2019 Trends in Cancer 5(1):66-78. IPF2018: 9.232.

5.       van den Berg CW, Ritsma L, Avramut MC, Wiersma LE, van den Berg B, Leuning DG, Lievers E, Koning M, Vanslambrouck JM, Koster AJ, Howden SE, Takasato M, Little MH, Rabelink TJ. Renal subcapsular transplantation of PSC derived kidney organoids induces neo-vasculogenesis and significant glomerular and tubular maturation in vivo. 2018 Stem Cell Reports10(3):751-765. IPF2018: 5.499

6.       Prunier C*, Chen N*, Ritsma L**, Vrisekoop N**. Procedures and applications of long-term intravital microscopy. 2017 Methods 128:52-64. IPF2017: 3.998

7.       Ritsma L, Dey-Guha I, Talele N, Sole X, Salony, Chowdhury J, Ross KN, Ramaswamy S. Integrin β1 activation induces an anti-melanoma host response. 2017 Plos One 12(4):e0175300. IPF2017: 2.766

8.       Van Grinsven E*, Prunier C*, Vrisekoop N**, Ritsma L**. Two-photon intravital microscopy animal preparation protocol to study cellular dynamics in pathogenesis. 2017 Methods Mol Biol 1563:51-71 (corresponding author). IPF2017: 2.02

9.       Frentzas S , Bridgeman V, Simoneau E, Vermeulen P, Foo S, Wotherspoon A, Gao Z, Shi Y, Van den Eynden G, Salman A, Lazaris A, Daley F, Gazinska P, Berg T, ltahir Z, Peckitt C, Ritsma L, van Rheenen J, Khashper A, Brown G, Nystrom H, Sund M, Loyer E, Dirix L, Metrakos P, Cunningham D, Kostaras E, Nathan M, Van Laere S, Tan X, Reynolds A. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. 2016 Nature Med 22(11):1294-1302. IPF2016: 29.886

10.   Salony, Solé X, Alves CP, Dey-Guha I, Ritsma L, Boukhali M, Lee JH, Chowdhury J, Ross KN, Haas W, Vasudevan S, Ramaswamy S. AKT Inhibition Promotes Nonautonomous Cancer Cell Survival. 2016 Mol Cancer Ther 15(1):142-53. IPF2016: 5.764

11.   Hughes SK, Oudin MJ, Tadros J, Neil J, Del Rosario A, Joughin BA, Ritsma L, Wyckoff J, Vasile E, Eddy R, Philippar U, Lussiez A, Condeelis JS, van Rheenen J, White F, Lauffenburger DA, Gertler FB. PTP1B-dependent regulation of receptor tyrosine kinase signaling by the actin-binding protein Mena. 2015 Mol Biol Cell 26(21):3867-78. IPF2015: 4.037

12.   Alieva M, Ritsma L*, Giedt RJ, Weissleder R, van Rheenen J. Imaging windows for long-term intravital imaging: general overview and technical insights. 2014 Intravital 3(2)e29917.

13.   Ritsma L*, Ellenbroek SIJ*, Snippert HJ, Simons BD, Clevers H, van Rheenen J. Intestinal crypt homeostasis revealed at single stem cell level by in vivo live-imaging. 2014 Nature507(7492):362-5, highlighted in Cell Stem Cell (14:271-2) 2014. IPF2014: 41.456

14.   Ritsma L, Vrisekoop N, van Rheenen J. Cryosection labeling and Intravital Microscopy correlates in vivo imaging and histochemistry. 2013 Nature Communications Aug 17;4:2366. IPF2013: 11.711

15.   Fritz RD, Letzelter M, Reimann A, Martin K, Fusco L, Ritsma L, Ponsioen B, Fluri E, Schulte-Merker S, van Rheenen J, Pertz O. A versatile toolkit to produce sensitive FRET biosensors to visualize signaling in time and space. 2013 Science SignalingJul 23;6(285):rs12. IPF2013: 6.463

16.   Ritsma L*, Steller EJA*, Ellenbroek SIJ, Kranenburg O, Borel Rinkes I, van Rheenen J. Surgical implantation of an Abdominal Imaging Window for intravital microscopy. 2013 Nature Protocols Feb 21;8(3):583-94. IPF2013: 9.33

17.   Zomer A, Ellenbroek SIJ, Ritsma L, Beerling E, Vrisekoop N, van Rheenen J. Intravital imaging of cancer stem cell plasticity in mammary tumors. 2013 Stem Cells Mar;31(3):602-6. IPF2017: 4.334

18.   Ariotti S, Beltman JB, Chodaczek G, Hoekstra ME, van Beek AE, Gomez-Eerland R, Ritsma L, van Rheenen J, Maree AFM, Zal T, de Boer RJ, Haanen JBAG, Schumacher TNM. Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen. 2012 PNAS Nov 27;109(48):19739-44. IPF2012: 10.984

19.   Ritsma L*, Steller EJ*, Beerling E, Loomans CJM, Zomer A, Gerlach C, Vrisekoop N, Seinstra D, van Gurp L, Schäfer R, Raats DA, de Graaff A, Schumacher TN, de Koning EJP, Borel Rinkes IH, Kranenburg O*, van Rheenen J*. Intravital microscopy through an abdominal imaging window reveals steps during liver metastasis. 2012 Science Transl Med. Oct 31;4(158):ra145, highlighted in Science Transl Med (4(158):fs39) 2012, Cancer Discovery (2:1077) 2012, and recommended by F1000Prime. IPF2012: 9.15

20.   Ritsma L, Ponsioen B, van Rheenen J. Intravital imaging of cell signaling in mice. 2012 IntraVital Jul/Aug/Sep (1):2-10.

21.   Steller EJ*, Ritsma L*, Raats DA, Hoogwater FJ, Emmink BL, Govaert KM, Laoukili J, Rinkes IH, van Rheenen J, Kranenburg O. The death receptor CD95 activates the cofilin pathway to stimulate tumour cell invasion. 2011 EMBO Rep. Sept 1:12(9):931-7. IPF2011: 7.355

22.   Beerling E*, Ritsma L*, Vrisekoop N, Derksen PW, van Rheenen J. Intravital microscopy: new insights into metastasis of tumors. 2011 J Cell Sci. Feb 1:124(Pt 3):299-310. IPF2011: 6.64

23.   Gloerich M, Ponsioen b, Vliem MJ, Zhang Z, Zhao J, Kooistra MR, Price LS, Ritsma L, Zwartkruis FJ, Rehmann H, Jalink K, Bos JL. Spatial regulation of cyclic AMP-Epac1 signaling in cell adhesion by ERM proteins. 2010 Mol Cell Biol. Nov 30(22):5421-31. IPF2010: 6.43

24.   Leyman S, Sidani M, Ritsma L, Waterschoot D, Eddy R, Dewitte D, Debeir O, Decaestecker C, Vandekerckhove J, van Rheenen J, Ampe C, Condeelis J, van Troys M. Unbalancing the phosphatidylinositol-4,5-biphosphate-cofilin interaction impairs cell steering. 2009 Mol Biol Cell. Nov 20(21):4509-23. IPF2009: 5.567

25.   Ponsioen B, Gloerich M, Ritsma L, Rehmann H, Bos JL, Jalink K. Direct spatial control of Epac1 by cyclic AMP. 2009 Mol Cell Biol. May 29(10):2521-31. IPF2009: 6.67

*  Equal contribution


Funding and awards

Funding

2017     PI, LUF subsidy Leids Universiteits Fonds,                                                        €25K

2017     PI, CGC.nl consortium grant                                                                            €300K

2016     PI, Veni grant NWO – Netherlands Organization for Scientific Research                      €250K

2015     PI, Gisela Thier Fellowship LUMC, the Netherlands                                           €400K

2015     PI, Susan G. Komen postdoctoral fellowship Susan G Komen foundation, USA           $180K

2013     PI, Rubicon Fellowship NWO – Netherlands Organization for Scientific Research €127.7K

2008    PI, KWF Student Fellowship Dutch Cancer Foundation                                      €1200

2008     PI, Trajectum Scholarship University of Utrecht, the Netherlands                     €260    

 

Awards

2017     CGC.nl Junior PI                                                                                                         

2013     ESMI award for excellent PhD thesis 2013,                                                      €500

2013     CGDB PhD student award [Best article(s) published in the previous year], €250    

2013     AACR invasion and metastasis conference, scholar-in-training-award,             $1000

 


Contactgegevens

Leids Universitair Medisch Centrum
Gebouw 2
Kamer R-02-003

Einthovenweg 20
2333 ZC Leiden
Tel: 071 5269268

Postzone S-1-P
Postbus 9600
2300 RC Leiden

E-mail: l.m.a.ritsma@lumc.nl