Peter Häring

Brain tumour cells interconnect to a functional and resistant network

Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.

Correction of patient positioning errors based on in-line cone beam CTs: clinical implementation and first experiences

BackgroundThe purpose of the study was the clinical implementation of a kV cone beam CT (CBCT) for setup correction in radiotherapy.Patients and methodsFor evaluation of the setup correction workflow, six tumor patients (lung cancer, sacral chordoma, head-and-neck and paraspinal tumor, and two prostate cancer patients) were selected. All patients were treated with fractionated stereotactic radiotherapy, five of them with intensity modulated radiotherapy (IMRT). For patient fixation, a scotch cast body frame or a vacuum pillow, each in combination with a scotch cast head mask, were used. The imaging equipment, consisting of an x-ray tube and a flat panel imager (FPI), was attached to a Siemens linear accelerator according to the in-line approach, i.e. with the imaging beam mounted opposite to the treatment beam sharing the same isocenter. For dose delivery, the treatment beam has to traverse the FPI which is mounted in the accessory tray below the multi-leaf collimator. For each patient, a predefined number of imaging projections over a range of at least 200 degrees were acquired. The fast reconstruction of the 3D-CBCT dataset was done with an implementation of the Feldkamp-David-Kress (FDK) algorithm. For the registration of the treatment planning CT with the acquired CBCT, an automatic mutual information matcher and manual matching was used.Results and discussionBony landmarks were easily detected and the table shifts for correction of setup deviations could be automatically calculated in all cases. The image quality was sufficient for a visual comparison of the desired target point with the isocenter visible on the CBCT. Soft tissue contrast was problematic for the prostate of an obese patient, but good in the lung tumor case. The detected maximum setup deviation was 3 mm for patients fixated with the body frame, and 6 mm for patients positioned in the vacuum pillow. Using an action level of 2 mm translational error, a target point correction was carried out in 4 cases. The additional workload of the described workflow compared to a normal treatment fraction led to an extra time of about 10–12 minutes, which can be further reduced by streamlining the different steps.ConclusionThe cone beam CT attached to a LINAC allows the acquisition of a CT scan of the patient in treatment position directly before treatment. Its image quality is sufficient for determining target point correction vectors. With the presented workflow, a target point correction within a clinically reasonable time frame is possible. This increases the treatment precision, and potentially the complex patient fixation techniques will become dispensable.

Stereotactic Intensity-Modulated Radiation Therapy (IMRT) and Inverse Treatment Planning for Advanced Pleural Mesothelioma

Background and Purpose: Complex-shaped malignant pleural mesotheliomas (MPMs) with challenging volumes are extremely difficult to treat by conventional radiotherapy due to tolerance doses of the surrounding normal tissue. In a feasibility study, we evaluated if inversely planned stereotactic intensity-modulated radiation therapy (IMRT) could be applied in the treatment of MPM. Patients and Methods: Results: Conclusion: Patients and Methods: Eight patients with unresectable lesions were treated after failure of chemotherapy. All patients were positioned using noninvasive patient fixation techniques which can be attached to the applied extracranial stereotactic system. Due to craniocaudal extension of the tumor, it was necessary to develop a special software attached to the inverse planning program KonRad, which can connect two inverse treatment plans and consider the applied dose of the first treatment plan in the area of the matchline of the second treatment plan. Results: Except for one patient, in whom radiotherapy was canceled due to abdominal metastasis, treatment could be completed in all patients and was well tolerated. Median survival after diagnosis was 20 months and after IMRT 6.5 months. Therefore, both the 1-year actuarial overall survival from the start of radiotherapy and the 2-year actuarial overall survival since diagnosis were 28%. IMRT did not result in clinically significant acute side effects. By using the described inverse planning software, overor underdosage in the region of the field matchline could be prevented. Pure treatment time ranged between 10 and 21 min. Conclusion: This study showed that IMRT is feasible in advanced unresectable MPM. The presented possibilities of stereotactic IMRT in the treatment of MPM will justify the evaluation of IMRT in early-stage pleural mesothelioma combined with chemotherapy in a study protocol, in order to improve the outcome of these patients. Furthermore, dose escalation should be possible by using IMRT.Hintergrund und Ziel: Komplex geformte bösartige Pleuramesotheliome mit einem ausgedehnten Volumen sind aufgrund der Toleranzdosen des umgebenden Normalgewebes nur sehr schwierig mit Hilfe der konventionellen Strahlentherapie zu behandeln. In einer Machbarkeitsstudie wurde untersucht, ob sich die stereotaktisch geplante intensitätsmodulierte Strahlentherapie (IMRT) zur Behandlung maligner Pleuramesotheliome eignet. Patienten und Methodik: Acht Patienten mit nicht resektablen Tumoren wurden bei Tumorprogress nach Chemotherapie behandelt. Alle Patienten wurden mit Hilfe eines nichtinvasiven Positionierungssystems gelagert, das in Verbindung mit einem Ganzkörperstereotaxiesystem verwendet wird. Aufgrund der kraniokaudalen Ausdehnung der Tumoren war es notwendig, eine spezielle, mit dem inversen Planungsprogramm KonRad verbundene Software zu entwickeln, die zwei unterschiedliche Bestrahlungspläne zusammenfügen kann. Die Dosisverteilung des ersten Bestrahlungsplans wird bei der Erstellung des zweiten Bestrahlungsplans berücksichtigt. Ergebnisse: Die Behandlung ließ sich bei sieben Patienten vollständig durchführen und wurde gut toleriert. Lediglich bei einem Patienten musste sie wegen einer abdominellen Metastase abgebrochen werden. Das mediane Überleben nach Diagnosestellung betrug 20 Monate und nach IMRT 6,5 Monate. Sowohl das aktuarische 1-Jahres-Überleben bei Beginn der Strahlentherapie als auch das 2-Jahres-Überleben nach Diagnosestellung lagen bei 28%. Nach der IMRT-Behandlung wurden keine klinisch signifikanten akuten Nebenwirkungen festgestellt. Mit Hilfe der verwendeten inversen Planungssoftware konnten Über- und Unterdosierungen im Bereich des Feldanschlusses vermieden werden. Die eigentliche Behandlungszeit variierte zwischen 10 und 21 min. Schlussfolgerung: Diese Studie zeigt, dass die IMRT bei fortgeschrittenen nicht resektablen Pleuramesotheliomen durchführbar ist. Die Möglichkeiten der vorgestellten stereotaktischen IMRT-Technik rechtfertigen die Erstellung eines Studienprotokolls in frühen Tumorstadien kombiniert mit einer Chemotherapie. Damit könnte die Prognose der Patienten verbessert werden. Des Weiteren sollte durch die IMRT eine Dosiseskalation möglich sein.

Inverse Treatment Planning and Stereotactic Intensity- Modulated Radiation Therapy (IMRT) of the Tumor and Lymph Node Levels for Nasopharyngeal Carcinomas Description of Treatment Technique, Plan Comparison, and Case Study

Purpose: Inverse treatment planning and intensity-modulated radiation therapy (IMRT) promise advantages in the treatment of tumors of the head and neck region. Currently published studies use IMRT only in the treatment of the primary tumor. In these studies, the lymph nodes of the neck were treated using conventional techniques. The feasibility of an IMRT technique with allows treatment of the complete target volume, including the primary tumor and lymph nodes, without a beam split is described. Patient and Method: For inverse treatment planning, the KonRad planning system was used. The primary as well as the secondary PTV (bilateral lymph node levels) were treated with one intensity-modulated primary plan. To increase the dose in the primary PTV and suspicious lymph nodes, an intensity-modulated boost plan was performed. The “step and shoot” IMRT technique was used. A plan comparison between the described IMRT approach and an IMRT approach using a split-beam technique was performed focusing on the treatment time. A patient with a carcinoma of the nasopharynx was treated with curative intent by a combined radiochemotherapy. Results: The median total dose to the primary PTV was 70 Gy, to suspicious lymph nodes ≥ 66.0 Gy, and to the secondary PTV 52 Gy. The defined maximum doses to the organs at risk were not exceeded, and the median dose to the protected parotid gland amounted to 21 Gy. Comparison of the treatment time between both IMRT approaches revealed only a slightly shorter treatment time (1–3 min) for the split-beam IMRT technique without considering the remaining conventional treatment parts of the split-beam IMRT technique. The patient achieved a complete response, and 18 months after treatment no signs of recurrent disease are visible. Conclusions: IMRT allows the treatment of the target volumes with high doses combined with an excellent sparing of the organs at risk. The IMRT approach presented here makes the treatment of the whole target volume with a single-beam arrangement feasible and does not increase the treatment time compared to a split-beam IMRT technique. Treatment time was comparable to a conventional three-field technique combined with electrons. This IMRT technique can prevent over- or underdosage at field matchlines in the head and neck region and, moreover, is able to spare parotid glands and therefore better avoid xerostomia compared to conventional techniques.Hintergrund: Die Verwendung der inversen Bestrahlungsplanung und der intensitätsmodulierten Strahlentherapie (IMRT) verspricht Vorteile bei der Behandlung von Tumoren im HNO-Bereich. Die derzeit veröffentlichten Studien verwenden IMRT lediglich für die Region des Primärtumors und benutzen für die Bestrahlung der Lymphabflusswege konventionelle Techniken. In diesem Zusammenhang wird eine Technik vorgestellt, mit der es möglich ist, das gesamte Zielvolumen, d. h. den Primärtumor sowie die Lymphknoten, ohne Feldanschlüsse zu behandeln. Patient und Methode: Die inverse Bestrahlungsplanung erfolgte mit dem “KonRad”-Planungssystem. Sowohl das primäre als auch das sekundäre PTV (beidseitige Lymphabflusswege) wurden mit einem intensitätsmodulierten Plan behandelt. Um die Dosis im primären PTV und in den malignitätsverdächtigen Lymphknoten zu erhöhen, wurde ein intensitätsmodulierter Boost-Plan angefertigt. Dabei wurde die “step and shoot”-Tecnik verwendet. Es wurde ein Planvergleich bezüglich der Behandlungszeit zwischen der vorgestellten IMRT-Technik und einer IMRT-Technik, die Feldanschlüsse verwendet, vorgenommen. Ein Patient mit Nasopharynxkarzinom wurde in kurativer Absicht mit einer kombinierten Radiochemotherapie behandelt. Ergebnisse: Die mediane Gesamtdosis im primären PTV betrug 70 Gy, in den malignitätsverdächtigen Lymphknoten ≥ 60 Gy und im sekundären PTV 52 Gy (Abbildung 1, Tabelle 1). Die Maximaldosen der Risikostrukturen konnten eingehalten werden, und die mediane Dosis der geschonten Parotis betrug 21 Gy. Der Vergleich der Behandlungszeit zwischen beiden IMRT-Techniken (Tabelle 2) zeigte, dass die Behandlungszeit für die IMRT-Technik, die Feldanschlüsse verwendet, etwas geringer ist (1–3 min). Dabei ist die Zeit für die Behandlung der Lymphabflusswege noch nicht berücksichtigt. Der Patient zeigte eine komplette Rückbildung des Tumors, und 18 Monate nach Therapie gibt es kein Anzeichen für ein Rezidiv. Schlussfolgerungen: Mit Hilfe der IMRT ist es möglich, hohe Dosen im Bestrahlungsvolumen zu erzielen und gleichzeitig die Risikostrukturen sehr gut zu schonen. Die vorgestellte IMRT-Technik ermöglicht es, das gesamte Zielvolumen mit einer Feldabfolge zu behandeln, und führt nicht zu einer Verlängerung der Behandlungszeit im Vergleich zu einer IMRT-Technik, die Feldanschlüsse verwendet. Die Behandlungszeit ist vergleichbar mit einer konventionellen Drei-Felder-Technik in Kombination mit Elektronen. Durch Verwendung dieser IMRT-Technik können Über- oder Unterdosierungen durch Feldanschlüsse im Halsbereich vermieden werden. Darüber hinaus ist möglich, die Ohrspeicheldrüsen mit dieser Technik zu schonen und deshalb eine Mundtrockenheit im Vergleich zu konventionellen Techniken zu verhindern.

6 MV dosimetric characterization of the 160 MLC™, the new Siemens multileaf collimator

New technical developments constantly aim at improving the outcome of radiation therapy. With the use of a computer-controlled multileaf collimator (MLC), the quality of the treatment and the efficiency in patient throughput is significantly increased. New MLC designs aim to further enhance the advantages. In this article, we present the first detailed experimental investigation of the new 160 MLC, Siemens Medical Solutions. The assessment included the experimental investigation of typical MLC characteristics such as leakage, tongue-and-groove effect, penumbra, leaf speed, and leaf positioning accuracy with a 6 MV treatment beam. The leakage is remarkably low with an average of 0.37% due to a new design principle of slightly tilted leaves instead of the common tongue-and-groove design. But due to the tilt, the triangular tongue-and-groove effect occurs. Its magnitude of approximately 19% is similar to the dose defect measured for MLCs with the common tongue-and-groove design. The average longitudinal penumbra measured at depth d(max) = 15 mm with standard 100 x 100 mm2 fields is 4.1 +/- 0.5 mm for the central range and increases to 4.9 +/- 1.3 mm for the entire field range of 400 x 400 mm2. The increase is partly due to the single-focusing design and the large distance between the MLC and the isocenter enabling a large patient clearance. Regarding the leaf speed, different velocity tests were performed. The positions of the moving leaves were continuously recorded with the kilovoltage-imaging panel. The maximum leaf velocities measured were 42.9 +/- 0.6 mm/s. In addition, several typical intensity-modulated radiation therapy treatments were performed and the delivery times compared to the Siemens OPTIFOCUS MLC. An average decrease of 11% in delivery time was observed. The experimental results presented in this article indicate that the dosimetric characteristics of the 160 MLC are capable of improving the quality of dose delivery with respect to precision and dose conformity.

Dosimetrische verifikation von IMRT-gesamtplänen am Deutschen Krebsforschungszentrum Heidelberg

Zusammenfassung In dieser Arbeit wird eine Methode zur individuellen dosimetrischen Uberprufung von IMRT-Bestrahlungsplanen beschrieben. Am Deutschen Krebsforschungszentrum (DKFZ) wird die intensitatsmodulierte Strahlentherapie (IMRT) seit 1997 durchgefuhrt. 246 Patienten mit Tumoren im Kopf-Hals Bereich, der Wirbelsaule, der Prostata, der weiblichen Brust und Pleuramesotheliome wurden bisher bestrahlt. Jeder IMRT-Bestrahlungsplan wird in ein spezielles Verifikationsphantom ubertragen, dort neu berechnet und dosimetrisch verifiziert. Absolute Dosisverteilungen werden mit Verifikationsfilmen Kodak EDR gemessen und mit der Dosisberechnung verglichen. Nach Korrektur der optischen Dichte zur Dosis kann fur die Absolutdosisgenauigkeit der Filmdosimetrie gegenuber Ionisationskammermessungen ein Wert von ±2 % erreicht werden. Eine Visual C ++ -Software wurde entwickelt, um die Filmdosisverteilungen mit den Schichten des 3D-Dosiswurfels zu uberlagern und auszuwerten. Neben der Uberlagerung von Isodosen und Profilen in absoluten oder relativen Dosiseinheiten wird der Medianwert der Dosis innerhalb korrelierter ROIs zur quantitativen Dosisauswertung herangezogen. Hierbei wurden Abweichungen zwischen Messung und Rechnung von δD = −0,3 % bei einer Standardabweichung von ±2,3 % ermittelt. Die Zeit pro IMRT-Verifikation inklusive Datenverarbeitung, –Uberlagerung, -Auswertung und -Dokumentation konnte nach Einfuhrung der Verifikationssoftware auf unter 2 Stunden reduziert werden.

MR-guidance – a clinical study to evaluate a shuttle- based MR-linac connection to provide MR-guided radiotherapy

BackgroundThe purpose of this clinical study is to investigate the clinical feasibility and safety of a shuttle-based MR-linac connection to provide MR-guided radiotherapy.Methods/DesignA total of 40 patients with an indication for a neoadjuvant, adjuvant or definitive radiation treatment will be recruited including tumors of the head and neck region, thorax, upper gastrointestinal tract and pelvic region. All study patients will receive standard therapy, i.e. highly conformal radiation techniques like CT-guided intensity-modulated radiotherapy (IMRT) with or without concomitant chemotherapy or other antitumor medication, and additionally daily short MR scans in treatment position with the same immobilisation equipment used for irradiation for position verification and imaging of the anatomical and functional changes during the course of radiotherapy. For daily position control, skin marks and a stereotactic frame will be used for both imaging modalities. Patient transfer between the MR device and the linear accelerator will be performed with a shuttle system which uses an air-bearing patient platform for both procedures. The daily acquired MR and CT data sets will be digitally registrated, correlated with the planning CT and compared with each other regarding translational and rotational errors. Aim of this clinical study is to establish a shuttle-based approach for realising MR-guided radiotherapy for certain clinical situations. Second objectives are to compare MR-guided radiotherapy with the gold standard of CT image guidance for quality assurance of radiotherapy, to establish an appropiate MR protocol therefore, and to assess the possibility of using MR-based image guidance not only for position verification but also for adaptive strategies in radiotherapy.DiscussionCompared to CT, MRI might offer the advantage of providing IGRT without delivering an additional radiation dose to the patients and the possibility of optimisation of adaptive therapy strategies due to its superior soft tissue contrast. However, up to now, hybrid MR-linac devices are still under construction and not clinically applicable. For the near future, a shuttle-based approach would be a promising alternative for providing MR-guided radiotherapy, so that the present study was initiated to determine feasibility and safety of such an approach. Besides positioning information, daily MR data under treatment offer the possibility to assess tumor regression and functional parameters, with a potential impact not only on adaptive therapy strategies but also on early assessment of treatment response.

Measurements of characteristics of time pattern in dose delivery in step-and-shoot IMRT.

Background and Purpose:Although intensity-modulated radiotherapy (IMRT) has already shown its clinical benefit, there are some issues which are not yet fully understood. Among these is the question whether the protracted dose delivery due to the lowered dose rate has any radiobiological consequences. To investigate this question, an exact characterization of dose rate profiles in typical clinical plans is needed. Furthermore, such a characterization may lead to an increased knowledge how to improve IMRT technically.Material and Methods:A new IMRT phantom which allows precise measurement of up to nine points of interest simultaneously with pin-point ionization chambers was developed. To examine dose rates, a new software tool (GRAYHOUND) was developed which can measure doses in short time intervals of up to 0.5 s. 250 points in four clinical IMRT plans were examined. A set of parameters was defined to describe the dose rate profiles including the effective fraction time (eft, which is the percentage of the fraction time in which any dose is delivered to a specific point), and a quotient of the percentage of dose delivered in high dose pulses (> 0.01 Gy/s) divided by the percentage of fraction time needed to deliver this dose (dHD/tHD).Results:These quotients are excellent markers for the inhomogeneity of dose rate delivery in IMRT. In both parameters a wide variance in points of the same plan and between different plans was found. For example, eft ranged between 11.6% and 37.3% in high dose points and the time in which high dose rates are delivered to a single high dose point ranged between 3.6% and 10.1% of total fraction time.Conclusions:These data show a great inhomogeneity of dose rates not only between different plans but also between different points in the same plan. Biological investigations are needed to quantify the relevance of these inhomogeneities. The parameters which are introduced in this work may be suitable to compare different optimization algorithms in IMRT.Hintergrund und Ziel:Obwohl die Intensitätsmodulierte Strahlentherapie (IMRT) ihren klinischen Nutzen bereits zeigen konnte, harren einige grundlegende Fragestellungen noch immer ihrer Antwort: Beispielsweise konnte noch nicht zufriedenstellend gezeigt werden, ob die zeitliche Dosisprotrahierung zu strahlenbiologischen Konsequenzen führt, und wenn ja, zu welchen. Um diese Frage beantworten zu können, ist jedoch eine genaue Charakterisierung der Dosisratenprofile in Plänen aus der klinischen Anwendung vonnöten. Des Weiteren könnte eine solche Charakterisierung zu neuen Hinweisen bezüglich der technischen Optimierung der IMRT führen.Material und Methodik:Es wurde ein neues Phantom entwickelt, das die präzise Messung von bis zu neun Punkten gleichzeitig mittels Pin-Point-Ionisationskammern ermöglicht. Um Dosisraten in der erforderlichen Genauigkeit zu untersuchen, wurde die Software GRAYHOUND entwickelt, die die Dosis in Zeitintervallen von bis zu 0,5 s messen kann. Insgesamt wurden 250 Punkte in vier klinischen Plänen untersucht. Es wurden eine Reihe von Parametern definiert, um die Dosisratenprofile beschreiben zu können: 1. die effektive Fraktionszeit (eft, definiert als prozentualer Anteil der Fraktionszeit, in der ein Punkt tatsächlich Dosis erhält); 2. der Quotient aus dem Anteil der Fraktionsdosis, der in Hochdosispulsen appliziert wird (> 0,01 Gy/s), und dem Anteil der dafür notwendigen Fraktionszeit (dHD/tHD).Ergebnisse:Diese Parameter sind ausgezeichnete Marker für die zeitliche Inhomogenität der Dosisapplikation in der IMRT. Bei beiden Parametern wurden große Unterschiede sowohl innerhalb eines Plans als auch zwischen den verschiedenen Plänen beobachtet: Beispielsweise variierten eft zwischen 11,6% und 37,3% und der Anteil der Fraktionszeit, in dem Hochdosispulse (und damit der Hauptteil der Dosis) appliziert wurden, zwischen 3,6% und 10,1% der gesamten Fraktionszeit.Schlussfolgerung:Die Daten zeigen eine hohe Inhomogenität der zeitlichen Dosisratenapplikation sowohl innerhalb als auch zwischen den verschiedenen Plänen. Strahlenbiologische Untersuchungen müssen nun die klinische Bedeutung dieser Inhomogenitäten klären. Die hier vorgestellten Parameter könnten sich beim Vergleich verschiedener Optimierungsalgorithmen als nützlich erweisen.

The influence of breathing motion on intensity modulated radiotherapy in the step-and-shoot technique: Phantom measurements for irradiation of superficial target volumes

For intensity modulated radiotherapy (IMRT) of deep-seated tumours, dosimetric variations of the original static dose profiles due to breathing motion can be primarily considered as blurring effects known from conventional radiotherapy. The purpose of this dosimetric study was to clarify whether these results are transferable to superficial targets and to quantify the additional effect of fractionation. A solid polystyrene phantom and an anthropomorphic phantom were used for film and ion chamber dose measurements. The phantoms were installed on an electric driven device and moved with a frequency of 6 or 12 cycles per minute and an amplitude of 4 mm or 10 mm. A split beam geometry of two adjacent asymmetric fields and an IMRT treatment plan with 12 fields for irradiation of the breast were investigated. For the split beam geometry the dose modifications due to unintended superposition of partial fields were reduced by fractionation and completely smoothed out after 20 fractions. IMRT applied to the moving phantom led to a more homogeneous dose distribution compared to the static phantom. The standard deviation of the target dose which is a measure of the dose homogeneity was 10.3 cGy for the static phantom and 7.7 cGy for a 10 mm amplitude. The absolute dose values, measured with ionization chambers, remained unaffected. Irradiation of superficial targets by IMRT in the step-and-shoot technique did not result in unexpected dose perturbations due to breathing motion. We conclude that regular breathing motion does not jeopardize IMRT of superficial target volumes.

Tweety-homolog 1 drives brain colonization of gliomas

Early and progressive colonization of the healthy brain is one hallmark of diffuse gliomas, including glioblastomas. We recently discovered ultralong (>10 to hundreds of microns) membrane protrusions [tumor microtubes (TMs)] extended by glioma cells. TMs have been associated with the capacity of glioma cells to effectively invade the brain and proliferate. Moreover, TMs are also used by some tumor cells to interconnect to one large, resistant multicellular network. Here, we performed a correlative gene-expression microarray and in vivo imaging analysis, and identified novel molecular candidates for TM formation and function. Interestingly, these genes were previously linked to normal CNS development. One of the genes scoring highest in tests related to the outgrowth of TMs was tweety-homolog 1 (TTYH1), which was highly expressed in a fraction of TMs in mice and patients. Ttyh1 was confirmed to be a potent regulator of normal TM morphology and of TM-mediated tumor-cell invasion and proliferation. Glioma cells with one or two TMs were mainly responsible for effective brain colonization, and Ttyh1 downregulation particularly affected this cellular subtype, resulting in reduced tumor progression and prolonged survival of mice. The remaining Ttyh1-deficient tumor cells, however, had more interconnecting TMs, which were associated with increased radioresistance in those small tumors. These findings imply a cellular and molecular heterogeneity in gliomas regarding formation and function of distinct TM subtypes, with multiple parallels to neuronal development, and suggest that Ttyh1 might be a promising target to specifically reduce TM-associated brain colonization by glioma cells in patients. SIGNIFICANCE STATEMENT In this report, we identify tweety-homolog 1 (Ttyh1), a membrane protein linked to neuronal development, as a potent driver of tumor microtube (TM)-mediated brain colonization by glioma cells. Targeting of Ttyh1 effectively inhibited the formation of invasive TMs and glioma growth, but increased network formation by intercellular TMs, suggesting a functional and molecular heterogeneity of the recently discovered TMs with potential implications for future TM-targeting strategies.