🔬✨ Just in time for
#FluorescenceFriday
! Thrilled to share our preprint on an approach to battle brain tumors! How can we understand & target the cellular networks between neurons and yet incurable brain tumors? Dive into rabies-based retrograde tracing of glioblastoma! 🧠💡
Very happy to share our latest manuscript
@CellCellPress
with you:
TL;DR: Glioblastomas are incurable brain tumors colonizing the entire brain. We overlay molecular and functional data to uncover a hijacking of neuronal mechanisms driving invasion.
How do glioblastoma invade and colonize the entire brain ?
Overlaying molecular, structural and functional data helped us to uncover three layers of neuronal mechanisms driving glioblastoma invasion (). A thread 🧵: (1/24)
1/ We're thrilled to share our preprint on Deep3P - a new approach that takes us on a deep dive into the world of brain tumors, using three-photon microscopy and
#AI
. This exciting endeavor is brought to life together with the amazing
@Prevedel_Lab
!
Very honoured to have our work highlighted by the great
@michelle_monje
and
@Kathryn_RTaylor
at
@CellCellPress
() !
Thanks so much ! The metaphor of malignant pioneers exploring the brain is really great and distills our observations from in vivo imaging.
Thrilled to receive the
#BIALAwardinBiomedicine
2023🏆! This achievement is a a testament to the hard work and dedication of all collaborators and our supportive institutions. Special thanks to the teams at
@UniHeidelberg
,
@DKFZ
,
@uniklinik_hd
, and our partners globally. Our
🏆And the winning paper of the
#BIALAwardinBiomedicine
2023 edition is “Glutamatergic synaptic input to glioma cells drives brain tumour progression", published in 2019 in
@Nature
, co-authored by 29 international researchers, led by
@VarunVenkatara2
, Frank Winkler-
@Winkler_Lab
,
🚀 The
@VarunVenkatara2
lab is excited to be at
#SNO2023
in Vancouver!
@StellaSoyka
will unveil our latest in deep intravital three-photon imaging of brain tumors and their microenvironment, correlative MRI and more, Saturday 8:05 AM in Room 118-120. 🌟
🤝 Delighted to co-chair
We are exited to share our discovery of excitatory synapses between neurons and tumor cells in brain metastases of breast cancer & melanoma. The groundbreaking study co-led by
@VarunVenkatara2
and me, with Thomas Kuner &
@WinklerLab
:
#CancerNeuroscience
Not satisfied with the amazing EM images showing that invading glioma cells form synapses with neurons,
@VarunVenkatara2
is developing three-photon microscopy to go deeper and reach these cells invading the corpus callosum.
#EANO2023
🎆Lighting up your
#FluorescenceFriday
and unmasking the invisible enemy within🧠💡. Our latest video shows how brain tumor cells craft cunning networks within white matter tracts to 'hide' in plain sight. Curious for more? Dive into our Deep3P preprint below!
#CancerNeuroscience
1/ We're thrilled to share our preprint on Deep3P - a new approach that takes us on a deep dive into the world of brain tumors, using three-photon microscopy and
#AI
. This exciting endeavor is brought to life together with the amazing
@Prevedel_Lab
!
Terrific talk by the amazing
@michelle_monje
and great discussion afterwards in the 'Cancer Neuroscience Seminar Series'. It was an honour to have you here ! Looking forward to the next developments of this exciting new field !
It was a pleasure to write a commentary () for
@trendscancer
about the recently published manuscript from Ben Deneen's lab in Neuron () ! Exciting times to study neuron-tumor networks !
#CancerNeuroscience
@CellPressNews
@CellCellPress
@HeidelbergU
The evolution of brain tumor networks. Learn more about the 'sociology' of brain tumors. See here how the brain is invaded by pioneering glioma cells to evolve into an interconnected network. More soon !
Thanks
@NatureRevCancer
for the great summary of our work !
Check out our recent manuscript
@CellCellPress
() and our Perspective article
@NatureRevCancer
() to learn more about multicellular tumor networks !
Our Aug issue, out NOW! With articles on nonsense-mediated RNA decay, diet interventions as
#therapy
,
#polyamines
& disconnecting multicellular networks in brain
#tumours
! Plus, a World View on what cancer survivors can teach researchers.
💌
@natrescancer
🧠 Exciting news from our latest research published in
@JAMANetworkOpen
! We've explored the performance of Large Language Models (LLMs) in neurology board-style exams. The results? Fascinating implications for AI in healthcare and neurology in specific:
I would like to thank everyone involved in this work which could not have been possible without the joint enormous efforts by everyone involved ! It was a great journey and I am looking forward to the next steps ! (24/24)
@NatureRevCancer
The power of intravital imaging: Communicating brain tumor networks as seen with in vivo two-photon 3D calcium imaging 😃 But it is even more complex ! More soon !
How do glioblastoma invade and colonize the entire brain ?
Overlaying molecular, structural and functional data helped us to uncover three layers of neuronal mechanisms driving glioblastoma invasion (). A thread 🧵: (1/24)
🔬🧠😎 Excellent technology feature highlighting the new movement towards
#SmartMicroscopes
for
#Biology
. Including work by us and many other outstanding laboratories such as
@IlariaTesta4
,
@Prevedel_Lab
, Pardo-López and Keller. Check it out!
How do glioblastoma invade and colonize the entire brain ?
Overlaying molecular, structural and functional data helped us to uncover three layers of neuronal mechanisms driving glioblastoma invasion (). A thread 🧵: (1/24)
How do glioblastoma invade and colonize the entire brain ?
Overlaying molecular, structural and functional data helped us to uncover three layers of neuronal mechanisms driving glioblastoma invasion (). A thread 🧵: (1/24)
It is very exciting to see that recent work by
@roelverhaak
and
@fsvarn
could confirm that neuronal signaling was indeed associated with a more invasive phenotype of human glioblastoma upon recurrence () (21/24)
Highly interesting
#CancerNeuroscience
work further illustrating the important role of the nervous system in the tumor microenvironment and even influencing immunosurveillance !
7/We also found two new vascular invasion route within the densely packed corpus callosum ! Glioblastoma cells can extend their neurite-like processes to establish a connection to blood vessels, and subsequently, relocate their cell bodies closer to these vessels.
@CellPressNews
@CellCellPress
@HeidelbergU
TL;DR: Glioblastoma hijacks neuronal mechanisms for invasion. We find three neuronal layers: a molecular neuronal-like cell state driving glioblastoma invasion, neuronal-like cellular mechanisms and neuron-glioma synapses driving neurite-like sprouting of tumor microtubes.
3/So far, we could only investigate the behavior of tumor cells in the superficial layers of the cortex using two-photon microscopy. Now, we venture into the depths of the corpus callosum to study glioblastoma biology.
The fourth winning
@CancerGrand
team is a second (!) team for the Solid Tumors in Children challenge: Team PROTECT, led by Stefan Pfister (
@KiTZ_HD
) - congratulations!
Previously, we saw a subpopulation of glioblastoma cells was connected with each other via gap junctions while other tumor cells appeared unconnected . The tumor-tumor network was resistant toward therapy. But what is the role of the seemingly unconnected tumor cells ? (2/24)
Spent a productive and very fun week with the
@jug_lab
at the Human Technopole in Milan!Many thanks to
@florianjug
for hosting me and especially
@ashesh0
for helping me move further with our project😊Can’t wait to share results of our collaborative efforts soon!
@VarunVenkatara2
Surprisingly, we found that some tumor cells not only talk to each other but also with astrocytes via gap junctions while the unconnected cells were neither connected to tumor cells nor astrocytes. (4/24)
Using in vivo timelapse imaging in xenograft models, we could identify tumor cells not connected to astrocytes and other tumor cells as drivers of glioblastoma invasion. (5/24)
To characterize molecular and functional glioblastoma cell states we used a combination of in vivo imaging and single cell RNA-sequencing with the dye SR101 that could distinguish tumor-connected and and tumor-unconnected glioblastoma cells. (3/24)
4/Utilizing a powerful trifecta of three-photon microscopy, adaptive optics for high image resolution, and AI for denoising, we've journeyed further into glioblastoma. We've attained an unprecedented 1.2 mm imaging depth to peer into brain tumor biology with high resolution.
How do glioblastoma invade and colonize the entire brain ?
Overlaying molecular, structural and functional data helped us to uncover three layers of neuronal mechanisms driving glioblastoma invasion (). A thread 🧵: (1/24)
New Cell article uses
#DeepLearning
enabled intravital subcellular time-lapse imaging (DeepISTI) to reveal neuron-like glioblastoma behavior driving tumor invasion, with help from Nikon's Enhance_ai software to enhance signal and reduce phototoxicity:
Our work can only be a small puzzle piece in a very exciting, emerging area of
#CancerNeuroscience
research. It is clear that we need to study these incurable brain tumors in a multidisciplinary fashion... (22/24)
Leveraging in vivo two photon microscopy with SR101 as connectivity marker we could demonstrate that tumor cell/astrocyte-unconnected glioblastoma cells evolve to tumor cell/astrocyte-connected glioblastoma cells over time. (7/24)
8/They behave much like climbers ascending a mountain.The neurite-like processes act as their 'ropes', and once they have that hold, they pull their 'base camp' closer to this new foothold. Glioblastoma cells may also establish a more comprehensive interaction with blood vessels:
9/, attaching both their neurite-like processes and cell bodies to these vessels. In this scenario, the cells utilize the blood vessels as a type of 'perivascular highway', effectively leveraging them for mobility and dissemination.
6/Deep3P has granted us fascinating insights. Unveiling perivascular invasion as a primary invasion pathway into the corpus callosum while glioma invasion within the cortex is only mediated to a small portion via perivascular mechanisms.
Lastly, we wanted to understand whether neuron-glioma synapses that we previously described ()also influence tumor microtube genesis and dynamics.And indeed ! Neuronal activity increased tumor microtube genesis and dynamics as well as invasion speed.(14/24)
5/Our research also taps into the third-harmonic generation signal, classified using tailored machine learning. This magnifies our ability to image both the tumor and its surrounding environment of blood vessels and myelinated axonal tracts.
If you are interested in the relationship between the structure and function of neurons, see this new study from our lab that correlates electron microscopy connectomics of the
#cerebellum
with molecular labels, using detergent-free scFv-based immunofluorescence.
#VEM
@Harvard
👇
What molecular cell states are now associated with invasion ? Using different classifications, we see that neuronal-like and neural progenitor-like/oligodendrocyte-precursor are enriched in the glioblastoma subpopulation driving invasion. (8/24)
10/Our study has also revealed the existence of intricate networks formed by glioblastoma cells, intertwined within the compact myelinated tracts of the corpus callosum, opening new avenues for further exploration.
11/With Deep3P, we can finally demystify why traditional MRI struggles to offer a comprehensive view of invaded areas. While changes aren't detectable with diffusion-weighted imaging, we have discovered that microscopic tractography shows no changes in myelinated tracts.
Next, we wanted to understand whether these connectivity states can be distinguished and how they evolve over time. scRNAseq showed that they can be molecularly separated and potentially transition from unconnected to connected tumor cells over time. (6/24)
12/Interestingly, our research has defined an imaging biomarker of white matter disruption during early glioblastoma colonization marking an interesting starting point for clinical imaging biomarker development.
We analyzed the scanning behaviour of tumor microtubes in more depth and found that this could be described a Levy-like movement pattern, a search-efficient mechanism that could previously also be seen in animal predators looking for scarce sources of food. (12/24)
Does the molecular neuronal-like cell state translate to neuronal cellular patterns of invasion ? We adapted restoration microscopy algorithms together with in-vivo two-photon imaging to follow small neurite-like processes called tumor microtubes. (9/24)
Taken together, we find three neuronal layers: a molecular neuronal-like cell state driving glioblastoma invasion, neuronal-like cellular mechanisms and neuron-glioma synapses driving neurite-like sprouting of tumor microtubes. (18/24)
How do single glioblastoma cells evolve over time on a molecular, cellular, connectivity and functional level ? How does the microenvironment change in parallel ? And very importantly: How do these results translate to the clinic ? (20/24)
How do glioblastoma invade and colonize the entire brain ?
Overlaying molecular, structural and functional data helped us to uncover three layers of neuronal mechanisms driving glioblastoma invasion (). A thread 🧵: (1/24)
Observation with in vivo imaging revealed that three overall movement patterns could describe the invasion pattern, reminiscent of neuronal migration patterns during development: branching migration, locomotion and translocation. (13/24)
Genetic perturbation and pharmacological AMPA receptor inhibition led to reduced reduced tumor microtubes per cell, reduced branching points and overall reduced tumor microtube length. (17/24)
Using this approach, we found three mechanisms govering tumor microtube dynamics similar to neurites during path-finding: branching, protrusion and retraction. (10/24)
Investigating the mechanisms with 3D in vivo calcium imaging, we found that glioblastoma cells not only show calcium waves and whole-cell calcium transients but also calcium microdomains. (15/ )
Exciting work by
@Loom19321
and
@DavidEClapham
!
Serotoniergic axon-cilium synapses are discovered and extensively characterised. Where else can these non-canonical synapses be found and what are their roles in (patho)physiological contexts ?