Kaisa Lehti Group
Our research focuses on tumor microenvironment communication in cancer invasion, metastasis and drug resistance.
Cancer metastasis and recurrence rely on tumor dissemination and tissue (re)colonization by interchangeable modes of cell invasion and growth. Such cellular plasticity also contributes to anticancer drug resistance, representing a major challenge in cancer research and clinical practice. Multiple tumor microenvironment (TME) communication pathways have been discovered. However, it remains incompletely understood how tumor cells integrate changes in cell-cell interactions, soluble factors and cues or physical confines of the extracellular matrix (ECM) with cytoskeletal dynamics and intracellular signaling to produce TME-dependent, plastic responses controlling growth, invasion and drug resistance.
To date, our results have revealed distinct mechanisms of TME-dependent oncogenic receptor tyrosine kinase signalling, ECM remodelling and transmembrane protease - adhesion receptor crosstalk.
I. The fibrotic and inflammatory responses in cancer
The extracellular matrix (ECM) is a tissue compartment of the tumor microenvironment (TME) that not only serves as a physical scaffold, but also influences cancer and stromal cells through biochemical and biophysical cues. During cancer progression and chemotherapy treatment, the TME undergoes major changes affecting ECM composition and biomechanical properties, inducing fibrosis and inflammation.
In our group, we have a long-term interest in membrane-type matrix metalloproteinases (MT-MMPs) that are involved in modulation of the TME, thereby regulating cancer cell proliferation, invasion and dissemination. Our previous studies have for instance have described a phenotypic switch from collagen infiltration to lymphovascular invasion, linear collagen assembly and tumor cell aggregation upon co-expression of MT1-MMP/MMP14 and MT3-MMP/MMP16 in the most aggressive melanoma tumors.
In our current study, we investigate how the matrisome (a group of genes encoding core ECM proteins and ECM-associated proteins, including cytokines, chemokines and growth factors) changes upon disease progression and chemotherapy treatment in patients with ovarian high grade serous carcinoma (HGSC). In addition, we explore how fibrotic matrisome changes upon HGSC metastasis and chemotherapy can alter cancer cell functions and vice versa how the cancer cell alterations affect the ECM sensing and remodeling.
Fibroblasts in the Tumor Microenvironment: Shield or Spear?
Alkasalias T, Moyano-Galceran L, Arsenian-Henriksson M, Lehti K
Int J Mol Sci 2018 May;19(5):
Membrane-type matrix metalloproteases as diverse effectors of cancer progression.
Turunen SP, Tatti-Bugaeva O, Lehti K
Biochim Biophys Acta Mol Cell Res 2017 Nov;1864(11 Pt A):1974-1988
MMP16 Mediates a Proteolytic Switch to Promote Cell-Cell Adhesion, Collagen Alignment, and Lymphatic Invasion in Melanoma.
Tatti O, Gucciardo E, Pekkonen P, Holopainen T, Louhimo R, Repo P, et al
Cancer Res 2015 May;75(10):2083-94
Actin-associated protein palladin promotes tumor cell invasion by linking extracellular matrix degradation to cell cytoskeleton.
von Nandelstadh P, Gucciardo E, Lohi J, Li R, Sugiyama N, Carpen O, et al
Mol Biol Cell 2014 Sep;25(17):2556-70
II. Receptor tyrosine kinase signaling in cancer
The transmission of extracellular signals into the cell and to the nucleus ensuring downstream cellular responses, i.e. signaling transduction, allows cell-cell communication within varying TMEs. Receptor tyrosine kinases (RTK) are membrane receptors that sense extracellular cues and promote diverse signaling responses regulating normal cellular processes. In cancer, these receptors are frequently altered to promote malignant cancer cell behavior and thereby explored as targets for current and future therapies.
Using a genome-wide gain-of-function human kinome screen we identified novel MT1-MMP regulators, including two RTKs, namely fibroblast growth factor receptor 4 (FGFR4) and Eph receptor A2 (EphA2). Our studies have shown that cancer-associated FGFR4 polymorphism affects the activity of an FGFR4-MT1-MMP complex in cancer progression, and that an EphA2-MT1-MMP axis regulates cancer invasion. In addition, we have uncovered a mechanism of FGFR4 oncogenic activity via suppression of the stress-associated mammalian sterile20-like kinases (MST1/2)-induced apoptosis machinery in tumor cells with prominent HER/ERBB and FGFR4 signaling-driven proliferation.
Most recently we identified a switch in EphA2 signaling induced upon treatment of ovarian cancer cells with platinum chemotherapy and linked to increased treatment resistance. By inhibiting the kinases mediating this oncogenic signaling (RSK1/2), we could efficiently sensitize cells to the chemotherapy-induced apoptosis in 2D and 3D models of HGSC ex vivo as well as in vivo, presenting a novel approach of how to improve currently available therapies.
Based on these results, our ongoing research explores the mechanisms of the complex signaling crosstalk governed by FGFRs and the context-dependent Eph-ephrin system, as well as the regulation of these signals by interactions with both the MMPs and adhesion molecules in human ovarian breast and gastric carcinomas.
Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer.
Moyano-Galceran L, Pietilä EA, Turunen SP, Corvigno S, Hjerpe E, Bulanova D, et al
EMBO Mol Med 2020 04;12(4):e11177
Crosstalk Between Cancer Associated Fibroblasts and Cancer Cells in Scirrhous Type Gastric Cancer.
Miki Y, Yashiro M, Moyano-Galceran L, Sugimoto A, Ohira M, Lehti K
Front Oncol 2020 ;10():568557
FGFR4 phosphorylates MST1 to confer breast cancer cells resistance to MST1/2-dependent apoptosis
Turunen SP, Von Nandelstadh P, Öhman T, Gucciardo E, Seashore-ludlow B, Martins B, Rantanen V, Li H, Höpfner K, Östling P, Varjosalo M, Lehti K Cell death and differentiation 2019;26(12):2577-2593
Eph- and ephrin-dependent mechanisms in tumor and stem cell dynamics
Gucciardo E, Sugiyama N, Lehti K Cellular and molecular life sciences: CMLS 2014;71(19):3685-710
EphA2 cleavage by MT1-MMP triggers single cancer cell invasion via homotypic cell repulsion
Sugiyama N, Gucciardo E, Tatti O, Varjosalo M, Hyytiäinen M, Gstaiger M, Lehti K The Journal of cell biology 2013;201(3):467-84
EphA2 bears plasticity to tumor invasion.
Sugiyama N, Gucciardo E, Lehti K
Cell Cycle 2013 Sep;12(18):2927-8
FGF receptor-4 (FGFR4) polymorphism acts as an activity switch of a membrane type 1 matrix metalloproteinase-FGFR4 complex.
Sugiyama N, Varjosalo M, Meller P, Lohi J, Chan KM, Zhou Z, et al
Proc Natl Acad Sci U S A 2010 Sep;107(36):15786-91
Fibroblast growth factor receptor 4 regulates tumor invasion by coupling fibroblast growth factor signaling to extracellular matrix degradation.
Sugiyama N, Varjosalo M, Meller P, Lohi J, Hyytiäinen M, Kilpinen S, et al
Cancer Res 2010 Oct;70(20):7851-61
Project leader Sahar Salehi
In the Lehti lab, we use modern molecular and cell biology techniques to examine how surgical treatment, the extent of surgery and local anesthetics affect mesothelial inflammation and tumour cell phenotype and functions in epithelial ovarian cancer (EOC). Moreover, the effects of identified molecular pathways on aggressive tumour properties such as invasion and chemotherapy resistance of EOC cells are tested in functional ex vivo assays.
By prospectively collecting relevant tumour and blood samples from our clinical Phase III trial (IPLA-OVCA) (https://clinicaltrials.gov/ct2/show/NCT04065009), translational investigation of the key molecules and cellular mechanisms underlying the unfavorable patient responses to the surgical trauma are investigated in detail with the specific aims:
I. To examine if surgical peritoneal stress evolves during the course of surgery, as measured by pro-inflammatory cytokines and biomarkers in the mesothelium, tumour tissues and blood, coupled to analysis of the circulating tumour DNA
II. To test if intraperitoneally administered anti-inflammatory analgesics may reduce the (mesothelial) inflammation.
III. To use functional ex vivo assays for exploring how the above identified surgical tissue responses and induced or inhibited pathways affect the aggressive EOC cell functions and properties including tumour invasion and chemo-resistance.
The samples are collected at the following time points:
The samples are transported fresh and directly from the operating theatre Karolinska University Hospital to the Lehti lab, KI. Each included patient generates close to 300 subsamples after processing.
Epithelial ovarian cancer (EOC) constitute cancers with origin in the fallopian tube, ovary or peritoneum and is the gynecologic malignancy with the highest mortality rate. Most women are diagnosed with advanced stage disease (70%) at presentation, when EOC has exfoliated to the peritoneal cavity. In Sweden, 650 women are diagnosed annually. Strategies for prolonging lives of women with EOC, are widening with emerging targeted therapies. Albeit this development, surgery remains the cornerstone in the available treatment armamentarium. Undisputedly, radical and complete surgical resection of tumour in combination with medical treatment (platinum-based chemotherapy) confers the basis for best survival outcomes in patients with EOC. For this reason, an abrupt shift in surgical treatment algorithm to aggressive upfront radical surgery with high proficiency surgeons was implemented Karolinska University Hospital (KUH) in 2014. The Stockholm Ovarian Cancer Project (STOOVCA) began as a quality assurance project in women with advanced EOC in the Stockholm/Gotland Region. The aim was to assess surgical quality and outcomes (survival) before and after this abrupt shift in surgical treatment algorithm to aggressive upfront ultra-radical surgery. Our hypothesis for this clinical study was that a shift to primary ultra-radical surgery in a population confers superior survival in patients subjected to surgery, without compromising the total overall survival regardless of primary treatment. Contrary to expectation we found that a shift to ultra-radical upfront surgery in a population did not improve overall survival in surgically treated patients, and instead conferred an inferior 3-year survival in patients subjected to radical surgery.
In our other recently completed clinical randomized double-blinded and placebo-controlled pilot study, we hypothesized that due to the known anti-inflammatory effect of local anesthetics (LA), postoperative recovery would be facilitated. In 40 patients undergoing cytoreductive surgery, randomized to treatment with either perioperative intraperitoneal local anesthetics (experiment) or saline (control), we found that the time-interval from surgery to start of adjuvant chemotherapy, an endpoint associated with prolonged survival, was significantly reduced in the intraperitoneal local anesthetics group.
For this reason, further investigation with a an adequately powered Phase III trial started recruitment in September 2020.
Ultra-radical upfront surgery does not improve survival in women with advanced epithelial ovarian cancer; a natural experiment in a complete population.
Falconer H, Joneborg U, Krawiec K, Palsdottir K, Bottai M, Salehi S
Gynecol Oncol 2020 Oct;159(1):58-65
Intraperitoneal ropivacaine reduces time interval to initiation of chemotherapy after surgery for advanced ovarian cancer: randomised controlled double-blind pilot study.
Hayden JM, Oras J, Block L, Thörn SE, Palmqvist C, Salehi S, et al
Br J Anaesth 2020 05;124(5):562-570
IV. SARCOMA TUMOR MICROENVIRONMENT
Project leader Jordi Gonzalez-Molina
Sarcomas are a very diverse group of malignancies accounting for about 1% of adult and 15% of childhood cancers. Sarcomas arise from connective tissues and are typically rich in structural extracellular matrix (ECM) proteins such as fibrillar collagens. With the final goal of improving patient treatment, we are investigating the impact of the tumour microenvironment on sarcomagenesis and tumour development. In close collaboration with Dr Joseph Carlson’s team, we have recently identified the ECM and the tumour immune microenvironment (TIME) as potentially interregulated factors with prognostic value in uterine sarcomas. This has motivated us to further investigate the function of the ECM in sarcoma. We are currently working in two main sarcoma projects:
I. Impact of collagen biomechanics and microarchitecture on rhabdomyosarcoma metastasis potential.
II. Evolution and impact of the ECM and the TIME on uterine mesenchymal tumour development.
These studies involve an in-depth tissue characterisation combining multi-omics technologies with biomechanical and image analysis techniques. Moreover, we develop biomaterial-based 3D culture systems to mimic clinically relevant tissue features to functionally assess the mechanisms of action of potential novel biomarkers and therapeutic targets.
The extracellular fluid macromolecular composition differentially affects cell-substrate adhesion and cell morphology.
Gonzalez-Molina J, Mendonça da Silva J, Fuller B, Selden C
Sci Rep 2019 06;9(1):8505
Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes.
Binzer-Panchal A, Hardell E, Viklund B, Ghaderi M, Bosse T, Nucci MR, et al
Clin Cancer Res 2019 04;25(7):2155-2165
Extracellular fluid viscosity enhances liver cancer cell mechanosensing and migration.
Gonzalez-Molina J, Zhang X, Borghesan M, Mendonça da Silva J, Awan M, Fuller B, et al
Biomaterials 2018 09;177():113-124
MMP14 in Sarcoma: A Regulator of Tumor Microenvironment Communication in Connective Tissues.
Gonzalez-Molina J, Gramolelli S, Liao Z, Carlson JW, Ojala PM, Lehti K
Cells 2019 08;8(9):