Lars Magnus Holmgren

Lars Magnus Holmgren

Professor

Professor i tumörbiologi och föreståndare för SFO SciLifeLab vid KI. Forskning om vaskulär mekanosensing, AmotL2 och tumörinvasion.

E-postadress: lars.holmgren@ki.se
Besöksadress: J6:20 BioClinicum, Akademiska stråket 1, 17164 Solna
Postadress: K7 Onkologi-Patologi, K7 Forskning Holmgren, 171 77 Stockholm
Del av:

Om mig

  • Professor i tumörbiologi vid Karolinska Institutet 2008-
    Ordförande tema cancer, U2/Bioclinicum planering 2012-
    Ordförande hörandeförsamling, 2013
    Ordförande nomineringsförsamling, 2011-2013
    Koordinator EU-consortium EUCAAD, 2008-2012
    Medlem av advisory board Paoli Calmette Cancer Center, Marseille
    Utvärderare av forskning, Vetenskapsrådet, Cancerfonden, Fernströms stiftelse, Internationella anslag
    Studierektor doktorandutbildning, OnkPat, 2004-2014

Forskningsbeskrivning

  • Forskningen fokuserar på hur celler känner av och svarar på mekaniska krafter i vävnaden  och hur störningar i dessa processer driver kärlsjukdom och cancer.

    En central upptäckt är att AmotL2 fungerar som en mekanosensor i kärlendotelet, kopplad till VE-cadherin och kontraktila aktinfilament. Vi har visat att denna signalväg reglerar vaskulär inflammation och att dess störning bidrar till bildandet av abdominala aortaaneurysm (AAA). Inom cancerbiologin har vi kartlagt hur p60AmotL2-isoformen bryter epitelial polaritet och driver invasiv tumörprogression via YAP/TAZ-beroende mekanotransduktion.

    Gruppen arbetar längs tre huvudlinjer: (1) mekanosensing och kärlbiologi, inklusive AAA och endotelial homeostas; (2) tumörcellinvasion och epitelial plasticitet; samt (3) horisontell genöverföring som mekanism för tumörprogression. Vi kombinerar molekylär- och cellbiologi med prekliniska modeller, patientmaterial och SciLifeLab-infrastrukturer för NGS, bioinformatik och fenotypisk screening.

Undervisning

  • My teaching activities span undergraduate, graduate and postgraduate levels, with a primary focus on PhD education and postdoctoral mentorship within tumor biology, vascular biology and translational oncology.

    I have served as principal supervisor for 16 completed PhD theses and 15 postdoctoral researchers, and am currently supervising 3 postdoctoral fellows. My PhD students have gone on to independent academic positions, industry roles in biotech and pharma, and clinical research careers.

    At the institutional level, I served as Director of PhD Education at Cancer Center Karolinska (CCK) for a total of eight years (2001–2003, 2006–2012), overseeing a program encompassing 118 doctoral students across KI's cancer research units. I also served as a member of KI's Committee for Doctoral Education (2012–2016) and as Director of PhD Studies at the Department of Oncology-Pathology (2004–2014).

    Course contributions include graduate-level teaching in tumor biology, angiogenesis and cancer cell biology within KI's PhD program in Oncology-Pathology, as well as lecturing in international PhD courses and summer schools.

Utvalda publikationer

Artiklar

Alla övriga publikationer

Forskningsbidrag

  • Swedish Heart-Lung Foundation
    1 January 2025 - 31 December 2027
    Bakgrund: Forskning kring mekaniska krafter och deras inverkan på mänsklig hälsa och sjukdomar är avgörande för förståelsen av vaskulära sjukdomar och cancer. Vårt program fokuserar på proteinet AmotL2, som är en del av Angiomotin-familjen, och dess roll i mekanotransduktiva signalvägar som påverkar cellernas respons på mekaniska stimuli. Målsättning och Hypotes: Syftet är att utforska AmotL2:s inverkan på vaskulär sjukdomsutveckling, speciellt dess interaktioner med cellulära strukturer och signalvägar. Vi hypotetiserar att AmotL2, genom sitt samspel med transkriptionsfaktorn YAP1 och dess reglering av cellens cytoskeletaldynamik, är kritisk för kärlhälsa och sjukdom. Arbetsplan: Studien inkluderar: Molekylära och Cellulära Studier: Avancerad bildteknik och masspektrometri för att studera AmotL2:s interaktion med andra proteiner. Genetiska Studier: GWAS för att identifiera genetiska varianter som påverkar AmotL2. Djurmodeller: Musmodeller med specifik knockout av AmotL2 för att studera dess roll i utvecklingen av AAA. Kliniska Studier: Samarbeten med kliniska forskare för att översätta laboratoriefynd till klinisk praxis. Betydelse: Forskningen syftar till att avancera vår förståelse för hur mekaniska krafter påverkar vaskulär patologi och åldrande. Genom att fokusera på AmotL2, siktar vi på att upptäcka nya terapeutiska mål för att hantera och behandla vaskulära sjukdomar, vilket potentiellt kan minska den globala sjukdomsbördan. Resultaten kan leda till betydande framsteg i förebyggande, diagnos och behandling av vaskulära sjukdomar, vilket förbättrar kliniska utfall och patienters livskvalitet.
  • Swedish Cancer Society
    1 January 2024
    Invasive cancer cells represent a major challenge in cancer treatment, as they often lead to metastases and worsen patient survival. We have previously discovered a signaling pathway that activates cells' ability to invade surrounding tissues. Protein p60AmotL2 is activated by stress signals, which gives cancer cells the opportunity to break away from cell-cell contacts and spread in surrounding tissue. Our previous studies have shown that this protein is overexpressed in many invasive tumor types, such as colon, breast, prostate and glioblastoma tumors. The aim of the project is to develop low molecular weight substances to eliminate invasive cancer cells. The idea is that this type of treatment can be a complement to existing drugs to knock out tumor cells that could otherwise cause recurrence. The p60AmotL2 signaling chain is activated in many cancers, giving the therapy wide application. We use cancer cells with p60AmotL2 and expose them to different substances. We have identified 10 potential substances to eliminate p60AmotL2/invasive cancer cells. Much work remains, including chemically modifying the substances for optimal effectiveness and reduced toxicity. -Investigate the underlying mechanisms of p60AmotL2-induced proinvasive signaling pathways to understand how they contribute to tumor invasion. -Perform selection of drugs to identify potential inhibitors of p60AmotL2-induced invasion, prioritizing agents with high efficacy and low toxicity. -Evaluate efficacy and safety of the best drug candidates in additional disease-relevant models. -By achieving these goals, the project can contribute to developing new therapies that target invasive tumor cells, which can ultimately improve patient outcomes and survival rates.
  • Swedish Heart-Lung Foundation
    1 January 2023 - 31 December 2024
  • Swedish Research Council
    1 December 2022 - 30 November 2025
  • Swedish Cancer Society
    1 January 2021
    A large proportion of cancer tumors arise in so-called epithelial cells. These cells form a surface layer or membrane that separates different areas of our organs. During tumor transformation, some of these cells not only begin to divide uncontrollably, but can also break free from normal neighboring cells and then spread throughout the body and form daughter tumors, which are called metastases. Our research group has discovered how cells in these epithelial membranes are mechanically connected to each other and how tumor cells activate certain proteins to be able to connect free from this control in order to be able to invade surrounding tissue. We mainly study the occurrence and spread of colon and breast cancer. We use the latest techniques to analyze protein expression in model systems that we have established in the laboratory. With the help of so-called mass spectrometry, we can analyze all the cell's proteins and identify which are linked to malignancy. We can thus obtain a pattern or fingerprint of the proteins used by malignant tumor cells. We then use this knowledge to study which cancer drugs these particular cells are sensitive to. We do this in collaboration with Sci-Life, Stockholm. In our project, as I said, we will characterize the protein patterns that tumor cells exhibit when they spread in the body. We hope to be able to use this diagnostically, that is, to be able to better predict the patient's prognosis and to be able to more specifically tailor treatment to the individual's needs. The latter is in line with our program to develop drugs that more specifically kill invasive tumor cells. We have already identified two classes of drugs that alone or in combination can target malignant cells.
  • Swedish Heart-Lung Foundation
    1 January 2020 - 31 December 2022
  • Swedish Research Council
    1 January 2019 - 31 December 2022
  • How do mechanical signals affect cancer conversion?
    Swedish Cancer Society
    1 January 2018
    About 80% of all tumors arise from so-called epithelial cells. These are found in skin, breast, prostate, lungs etc. where they have an important barrier function etc. for our organs. In order to perform these functions, they must be polarized ie are unsymmetrical. It can be likened to a house that is unsymmetrical with a roof upwards and the ground down. Typical of malignant cells is that they have just lost this polarity. Despite this, one has not been able to demonstrate that it is a step in tumor transformation or just a side effect of this process. When a tumor grows, there are often many cells that do not have access to normal oxygen levels. They then activate a series of defense mechanisms to cope with these "tough" conditions. There is a clear link between low oxygen levels and malignancy. However, it is not entirely clear how this works mechanically. We have identified a completely new signal path that is activated by low oxygen levels and other stress signals. A protein we call p60 AmotL2 is activated by stress and the result is that the cells are depolarized. This causes them to become invasive and more malignant. 1. We want to understand how cancer cells become malignant 2. We want to test if p60AmotL2 can be used to predict the risk of metastasis. 3. We now have a unique system for selecting agents that can specifically target depolarized (malignant) tumor cells.
  • How do mechanical signals affect cancer conversion?
    Swedish Cancer Society
    1 January 2017
    About 80% of all tumors arise from so-called epithelial cells. These are found in skin, breast, prostate, lungs etc. where they have an important barrier function etc. for our organs. In order to perform these functions, they must be polarized ie are unsymmetrical. It can be likened to a house that is unsymmetrical with a roof upwards and the ground down. Typical of malignant cells is that they have just lost this polarity. Despite this, one has not been able to demonstrate that it is a step in tumor transformation or just a side effect of this process. When a tumor grows, there are often many cells that do not have access to normal oxygen levels. They then activate a series of defense mechanisms to cope with these "tough" conditions. There is a clear link between low oxygen levels and malignancy. However, it is not entirely clear how this works mechanically. We have identified a completely new signal path that is activated by low oxygen levels and other stress signals. A protein we call p60 AmotL2 is activated by stress and the result is that the cells are depolarized. This causes them to become invasive and more malignant. 1. We want to understand how cancer cells become malignant   2. We want to test if p60AmotL2 can be used to predict the risk of metastasis.   3. We now have a unique system for selecting agents that can specifically target depolarized (malignant) tumor cells.
  • Knut and Alice Wallenberg Foundation
    1 January 2017 - 1 January 2022
  • How does low oxygen levels or other stress affect cancer cells' ability to spread?
    Swedish Cancer Society
    1 January 2016
    About 80% of all tumors arise from so-called epithelial cells. These are found in skin, breast, prostate, lungs etc. where they have an important barrier function etc. for our organs. In order to perform these functions, they must be polarized ie are unsymmetrical. It can be likened to a house that is unsymmetrical with a roof upwards and the ground down. Typical of malignant cells is that they have just lost this polarity. Despite this, one has not been able to demonstrate that it is a step in tumor transformation or just a side effect of this process. When a tumor grows, there are often many cells that do not have access to normal oxygen levels. They then activate a series of defense mechanisms to cope with these "tough" conditions. There is a clear link between low oxygen levels and malignancy. However, it is not entirely clear how this works mechanically. We have identified a completely new signal path that is activated by low oxygen levels and other stress signals. A protein we call p60 AmotL2 is activated by stress and the result is that the cells are depolarized. This causes them to become invasive and more malignant. 1. We want to understand how cancer cells become malignant   2. We want to test if p60AmotL2 can be used to predict the risk of metastasis.   3. We now have a unique system for selecting agents that can specifically target depolarized (malignant) tumor cells.
  • How does low oxygen levels or other stress affect cancer cells' ability to spread?
    Swedish Cancer Society
    1 January 2015
    About 80% of all tumors arise from so-called epithelial cells. These are found in skin, breast, prostate, lungs etc. where they have an important barrier function etc. for our organs. In order to perform these functions, they must be polarized ie are unsymmetrical. It can be likened to a house that is unsymmetrical with a roof upwards and the ground down. Typical of malignant cells is that they have just lost this polarity. Despite this, one has not been able to demonstrate that it is a step in tumor transformation or just a side effect of this process. When a tumor grows, there are often many cells that do not have access to normal oxygen levels. They then activate a series of defense mechanisms to cope with these "tough" conditions. There is a clear link between low oxygen levels and malignancy. However, it is not entirely clear how this works mechanically. We have identified a completely new signal path that is activated by low oxygen levels and other stress signals. A protein we call p60 AmotL2 is activated by stress and the result is that the cells are depolarized. This causes them to become invasive and more malignant. 1. We want to understand how cancer cells become malignant   2. We want to test if p60AmotL2 can be used to predict the risk of metastasis.   3. We now have a unique system for selecting agents that can specifically target depolarized (malignant) tumor cells.
  • Swedish Research Council
    1 January 2015 - 31 December 2018
  • How does low oxygen levels or other stress affect cancer cells' ability to spread?
    Swedish Cancer Society
    1 January 2014
    About 80% of all tumors arise from so-called epithelial cells. These are found in skin, breast, prostate, lungs etc. where they have an important barrier function etc. for our organs. In order to perform these functions, they must be polarized ie are unsymmetrical. It can be likened to a house that is unsymmetrical with a roof upwards and the ground down. Typical of malignant cells is that they have just lost this polarity. Despite this, one has not been able to demonstrate that it is a step in tumor transformation or just a side effect of this process. When a tumor grows, there are often many cells that do not have access to normal oxygen levels. They then activate a series of defense mechanisms to cope with these "tough" conditions. There is a clear link between low oxygen levels and malignancy. However, it is not entirely clear how this works mechanically. We have identified a completely new signal path that is activated by low oxygen levels and other stress signals. A protein we call p60 AmotL2 is activated by stress and the result is that the cells are depolarized. This causes them to become invasive and more malignant. 1. We want to understand how cancer cells become malignant 2. We want to test if p60AmotL2 can be used to predict the risk of metastasis. 3. We now have a unique system for selecting agents that can specifically target depolarized (malignant) tumor cells.
  • Swedish Research Council
    1 January 2012 - 31 December 2014
  • Swedish Research Council
    1 January 2009 - 31 December 2011

Anställningar

  • Professor, Tumörbiologi, Onkologi-Patologi, Karolinska Institutet, 2008-

Examina och utbildning

  • Docent, Tumörbiologi, Karolinska Institutet, 1998

Uppdrag

  • Prefekt, Onkologi-Patologi, Karolinska Institutet, 2021-2025

Nyheter från KI

Kalenderhändelser från KI