Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma

Flavia Bernardi; Jacob Torrejon; Irene Basili; Randy Van Ommeren; Véronique Marsaud; Hua Yu; Julie Talbot; Judith Souphron; Emilie Indersie; Antoine Forget; Benjamin Bonneau; Alexane Massiot; Coralie Alcazar; Laurine Figeac; Emma Bonerandi; Gabriele Cancila; Olga Sirbu; Navneesh Yadav; Dinesh Mohanakrishnan; Bérangère Lombard; Damarys Loew; Patrick Poullet; Stephane Liva; Marta Lovino; I-Hsuan Lin; Takuma Nakashima; Tarek Gharsalli; Paul Antoine Nicolas; Naoji Yubuki; Roberto A Ribas; Benoit Colsch; Emeline Chu-Van; Florence Castelli; Julio Lopes Sampaio; Sophie Leboucher; Charlene Lasgi; Laetitia Besse; Marie-Noëlle Soler; Valentina Lo Re; Nathalie Planque; Namal Abeysundara; Polina Balin; Hao Wang; Haipeng Su; Xiaochong Wu; Florence M G Cavalli; Olivier Saulnier; Elisa Ficarra; Lucia Di Marcotullio; Kohei Kumegawa; Reo Maruyama; Daisuke Kawauchi; Daniel Picard; Marc Remke; Laurent Riffaud; Chloé Puiseux; Yassine Bouchoucha; Sophie Huybrechts; Marie Simbozel; Franck Bourdeaut; Pascale Varlet; Stéphanie Puget; Thomas Blauwblomme; Mamy Andrianteranagna; Julien Masliah Planchon; Aurelien Dugourd; Julio Saez-Rodriguez; Emmanuel Barillot; Nicolas Servant; Loredana Martignetti; Jeremy Rich; Marcel Kool; Stefan M Pfister; Sameer Agnihotri; Hiromichi Suzuki; Marjorie Fanjul; Won-Jing Wang; Jin-Wu Tsai; Ramon C Sun; Kévin Beccaria; Christelle Dufour; Jean-Emmanuel Sarry; Kulandaimanuvel Antony Michealraj; Michael D Taylor; Olivier Ayrault

doi:10.1016/j.ccell.2025.12.012

Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma

Flavia Bernardi
, Jacob Torrejon
, Irene Basili
, Randy Van Ommeren
, Véronique Marsaud
, Hua Yu
, Julie Talbot
, Judith Souphron
, Emilie Indersie
, Antoine Forget
, Benjamin Bonneau
, Alexane Massiot
, Coralie Alcazar
, Laurine Figeac
, Emma Bonerandi
, Gabriele Cancila
, Olga Sirbu
, Navneesh Yadav
, Dinesh Mohanakrishnan
, Bérangère Lombard

Damarys Loew, Patrick Poullet, Stephane Liva, Marta Lovino, I-Hsuan Lin, Takuma Nakashima, Tarek Gharsalli, Paul Antoine Nicolas, Naoji Yubuki, Roberto A Ribas, Benoit Colsch, Emeline Chu-Van, Florence Castelli, Julio Lopes Sampaio, Sophie Leboucher, Charlene Lasgi, Laetitia Besse, Marie-Noëlle Soler, Valentina Lo Re, Nathalie Planque, Namal Abeysundara, Polina Balin, Hao Wang, Haipeng Su, Xiaochong Wu, Florence M G Cavalli, Olivier Saulnier, Elisa Ficarra, Lucia Di Marcotullio, Kohei Kumegawa, Reo Maruyama, Daisuke Kawauchi, Daniel Picard, Marc Remke, Laurent Riffaud, Chloé Puiseux, Yassine Bouchoucha, Sophie Huybrechts, Marie Simbozel, Franck Bourdeaut, Pascale Varlet, Stéphanie Puget, Thomas Blauwblomme, Mamy Andrianteranagna, Julien Masliah Planchon, Aurelien Dugourd, Julio Saez-Rodriguez, Emmanuel Barillot, Nicolas Servant, Loredana Martignetti, Jeremy Rich, Marcel Kool, Stefan M Pfister, Sameer Agnihotri, Hiromichi Suzuki, Marjorie Fanjul, Won-Jing Wang, Jin-Wu Tsai, Ramon C Sun, Kévin Beccaria, Christelle Dufour, Jean-Emmanuel Sarry, Kulandaimanuvel Antony Michealraj^*, Michael D Taylor^*, Olivier Ayrault^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Medulloblastoma, the most common malignant brain tumor of childhood, exhibits significant biological complexity that demands deeper exploration. Here, we present a large multiomics dataset integrating data from 384 primary medulloblastoma patient samples across five omic layers: CpG methylome, transcriptome, proteome, phosphoproteome, and metabolome, paired with associated clinical metadata. Data integration revealed intertumoral heterogeneity of lipid metabolism across proteomic subtypes. Notably, while the MYC-FASN-SCD axis drives lipid biosynthesis, pathway inhibition elicits a compensatory escape mechanism in vivo through exogenous fatty acid uptake. Unexpectedly, we demonstrated that MYC triggers lipid storage, creating a unique dependency on lipid droplet-mitochondria communications to sustain tumor maintenance in vivo. Together, this comprehensive analysis reveals a targetable vulnerability downstream of MYC that constitutes a promising therapeutic approach to treat currently untreatable medulloblastoma subtypes.

Original language	English
Pages (from-to)	p383-404.e18
Journal	Cancer Cell
Volume	44
Issue number	2
Early online date	15 Jan 2026
DOIs	https://doi.org/10.1016/j.ccell.2025.12.012
Publication status	Published - 9 Feb 2026

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10.1016/j.ccell.2025.12.012

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Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma
Final published version, 23.6 MB
Licence: Taverne
Embargo ends: 15/07/26

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Bernardi, F., Torrejon, J., Basili, I., Van Ommeren, R., Marsaud, V., Yu, H., Talbot, J., Souphron, J., Indersie, E., Forget, A., Bonneau, B., Massiot, A., Alcazar, C., Figeac, L., Bonerandi, E., Cancila, G., Sirbu, O., Yadav, N., Mohanakrishnan, D., ... Ayrault, O. (2026). Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma. Cancer Cell, 44(2), p383-404.e18. https://doi.org/10.1016/j.ccell.2025.12.012

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title = "Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma",

abstract = "Medulloblastoma, the most common malignant brain tumor of childhood, exhibits significant biological complexity that demands deeper exploration. Here, we present a large multiomics dataset integrating data from 384 primary medulloblastoma patient samples across five omic layers: CpG methylome, transcriptome, proteome, phosphoproteome, and metabolome, paired with associated clinical metadata. Data integration revealed intertumoral heterogeneity of lipid metabolism across proteomic subtypes. Notably, while the MYC-FASN-SCD axis drives lipid biosynthesis, pathway inhibition elicits a compensatory escape mechanism in vivo through exogenous fatty acid uptake. Unexpectedly, we demonstrated that MYC triggers lipid storage, creating a unique dependency on lipid droplet-mitochondria communications to sustain tumor maintenance in vivo. Together, this comprehensive analysis reveals a targetable vulnerability downstream of MYC that constitutes a promising therapeutic approach to treat currently untreatable medulloblastoma subtypes.",

author = "Flavia Bernardi and Jacob Torrejon and Irene Basili and \{Van Ommeren\}, Randy and V{\'e}ronique Marsaud and Hua Yu and Julie Talbot and Judith Souphron and Emilie Indersie and Antoine Forget and Benjamin Bonneau and Alexane Massiot and Coralie Alcazar and Laurine Figeac and Emma Bonerandi and Gabriele Cancila and Olga Sirbu and Navneesh Yadav and Dinesh Mohanakrishnan and B{\'e}rang{\`e}re Lombard and Damarys Loew and Patrick Poullet and Stephane Liva and Marta Lovino and I-Hsuan Lin and Takuma Nakashima and Tarek Gharsalli and Nicolas, \{Paul Antoine\} and Naoji Yubuki and Ribas, \{Roberto A\} and Benoit Colsch and Emeline Chu-Van and Florence Castelli and Sampaio, \{Julio Lopes\} and Sophie Leboucher and Charlene Lasgi and Laetitia Besse and Marie-No{\"e}lle Soler and \{Lo Re\}, Valentina and Nathalie Planque and Namal Abeysundara and Polina Balin and Hao Wang and Haipeng Su and Xiaochong Wu and Cavalli, \{Florence M G\} and Olivier Saulnier and Elisa Ficarra and \{Di Marcotullio\}, Lucia and Kohei Kumegawa and Reo Maruyama and Daisuke Kawauchi and Daniel Picard and Marc Remke and Laurent Riffaud and Chlo{\'e} Puiseux and Yassine Bouchoucha and Sophie Huybrechts and Marie Simbozel and Franck Bourdeaut and Pascale Varlet and St{\'e}phanie Puget and Thomas Blauwblomme and Mamy Andrianteranagna and Planchon, \{Julien Masliah\} and Aurelien Dugourd and Julio Saez-Rodriguez and Emmanuel Barillot and Nicolas Servant and Loredana Martignetti and Jeremy Rich and Marcel Kool and Pfister, \{Stefan M\} and Sameer Agnihotri and Hiromichi Suzuki and Marjorie Fanjul and Won-Jing Wang and Jin-Wu Tsai and Sun, \{Ramon C\} and K{\'e}vin Beccaria and Christelle Dufour and Jean-Emmanuel Sarry and Michealraj, \{Kulandaimanuvel Antony\} and Taylor, \{Michael D\} and Olivier Ayrault",

note = "Publisher Copyright: {\textcopyright} 2025",

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doi = "10.1016/j.ccell.2025.12.012",

language = "English",

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Bernardi, F, Torrejon, J, Basili, I, Van Ommeren, R, Marsaud, V, Yu, H, Talbot, J, Souphron, J, Indersie, E, Forget, A, Bonneau, B, Massiot, A, Alcazar, C, Figeac, L, Bonerandi, E, Cancila, G, Sirbu, O, Yadav, N, Mohanakrishnan, D, Lombard, B, Loew, D, Poullet, P, Liva, S, Lovino, M, Lin, I-H, Nakashima, T, Gharsalli, T, Nicolas, PA, Yubuki, N, Ribas, RA, Colsch, B, Chu-Van, E, Castelli, F, Sampaio, JL, Leboucher, S, Lasgi, C, Besse, L, Soler, M-N, Lo Re, V, Planque, N, Abeysundara, N, Balin, P, Wang, H, Su, H, Wu, X, Cavalli, FMG, Saulnier, O, Ficarra, E, Di Marcotullio, L, Kumegawa, K, Maruyama, R, Kawauchi, D, Picard, D, Remke, M, Riffaud, L, Puiseux, C, Bouchoucha, Y, Huybrechts, S, Simbozel, M, Bourdeaut, F, Varlet, P, Puget, S, Blauwblomme, T, Andrianteranagna, M, Planchon, JM, Dugourd, A, Saez-Rodriguez, J, Barillot, E, Servant, N, Martignetti, L, Rich, J, Kool, M, Pfister, SM, Agnihotri, S, Suzuki, H, Fanjul, M, Wang, W-J, Tsai, J-W, Sun, RC, Beccaria, K, Dufour, C, Sarry, J-E, Michealraj, KA, Taylor, MD & Ayrault, O 2026, 'Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma', Cancer Cell, vol. 44, no. 2, pp. p383-404.e18. https://doi.org/10.1016/j.ccell.2025.12.012

TY - JOUR

T1 - Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma

AU - Bernardi, Flavia

AU - Torrejon, Jacob

AU - Basili, Irene

AU - Van Ommeren, Randy

AU - Marsaud, Véronique

AU - Yu, Hua

AU - Talbot, Julie

AU - Souphron, Judith

AU - Indersie, Emilie

AU - Forget, Antoine

AU - Bonneau, Benjamin

AU - Massiot, Alexane

AU - Alcazar, Coralie

AU - Figeac, Laurine

AU - Bonerandi, Emma

AU - Cancila, Gabriele

AU - Sirbu, Olga

AU - Yadav, Navneesh

AU - Mohanakrishnan, Dinesh

AU - Lombard, Bérangère

AU - Loew, Damarys

AU - Poullet, Patrick

AU - Liva, Stephane

AU - Lovino, Marta

AU - Lin, I-Hsuan

AU - Nakashima, Takuma

AU - Gharsalli, Tarek

AU - Nicolas, Paul Antoine

AU - Yubuki, Naoji

AU - Ribas, Roberto A

AU - Colsch, Benoit

AU - Chu-Van, Emeline

AU - Castelli, Florence

AU - Sampaio, Julio Lopes

AU - Leboucher, Sophie

AU - Lasgi, Charlene

AU - Besse, Laetitia

AU - Soler, Marie-Noëlle

AU - Lo Re, Valentina

AU - Planque, Nathalie

AU - Abeysundara, Namal

AU - Balin, Polina

AU - Wang, Hao

AU - Su, Haipeng

AU - Wu, Xiaochong

AU - Cavalli, Florence M G

AU - Saulnier, Olivier

AU - Ficarra, Elisa

AU - Di Marcotullio, Lucia

AU - Kumegawa, Kohei

AU - Maruyama, Reo

AU - Kawauchi, Daisuke

AU - Picard, Daniel

AU - Remke, Marc

AU - Riffaud, Laurent

AU - Puiseux, Chloé

AU - Bouchoucha, Yassine

AU - Huybrechts, Sophie

AU - Simbozel, Marie

AU - Bourdeaut, Franck

AU - Varlet, Pascale

AU - Puget, Stéphanie

AU - Blauwblomme, Thomas

AU - Andrianteranagna, Mamy

AU - Planchon, Julien Masliah

AU - Dugourd, Aurelien

AU - Saez-Rodriguez, Julio

AU - Barillot, Emmanuel

AU - Servant, Nicolas

AU - Martignetti, Loredana

AU - Rich, Jeremy

AU - Kool, Marcel

AU - Pfister, Stefan M

AU - Agnihotri, Sameer

AU - Suzuki, Hiromichi

AU - Fanjul, Marjorie

AU - Wang, Won-Jing

AU - Tsai, Jin-Wu

AU - Sun, Ramon C

AU - Beccaria, Kévin

AU - Dufour, Christelle

AU - Sarry, Jean-Emmanuel

AU - Michealraj, Kulandaimanuvel Antony

AU - Taylor, Michael D

AU - Ayrault, Olivier

PY - 2026/2/9

Y1 - 2026/2/9

N2 - Medulloblastoma, the most common malignant brain tumor of childhood, exhibits significant biological complexity that demands deeper exploration. Here, we present a large multiomics dataset integrating data from 384 primary medulloblastoma patient samples across five omic layers: CpG methylome, transcriptome, proteome, phosphoproteome, and metabolome, paired with associated clinical metadata. Data integration revealed intertumoral heterogeneity of lipid metabolism across proteomic subtypes. Notably, while the MYC-FASN-SCD axis drives lipid biosynthesis, pathway inhibition elicits a compensatory escape mechanism in vivo through exogenous fatty acid uptake. Unexpectedly, we demonstrated that MYC triggers lipid storage, creating a unique dependency on lipid droplet-mitochondria communications to sustain tumor maintenance in vivo. Together, this comprehensive analysis reveals a targetable vulnerability downstream of MYC that constitutes a promising therapeutic approach to treat currently untreatable medulloblastoma subtypes.

AB - Medulloblastoma, the most common malignant brain tumor of childhood, exhibits significant biological complexity that demands deeper exploration. Here, we present a large multiomics dataset integrating data from 384 primary medulloblastoma patient samples across five omic layers: CpG methylome, transcriptome, proteome, phosphoproteome, and metabolome, paired with associated clinical metadata. Data integration revealed intertumoral heterogeneity of lipid metabolism across proteomic subtypes. Notably, while the MYC-FASN-SCD axis drives lipid biosynthesis, pathway inhibition elicits a compensatory escape mechanism in vivo through exogenous fatty acid uptake. Unexpectedly, we demonstrated that MYC triggers lipid storage, creating a unique dependency on lipid droplet-mitochondria communications to sustain tumor maintenance in vivo. Together, this comprehensive analysis reveals a targetable vulnerability downstream of MYC that constitutes a promising therapeutic approach to treat currently untreatable medulloblastoma subtypes.

U2 - 10.1016/j.ccell.2025.12.012

DO - 10.1016/j.ccell.2025.12.012

M3 - Article

C2 - 41544627

SN - 1535-6108

VL - 44

SP - p383-404.e18

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

Multiomic integration reveals tumoral heterogeneity of lipid dependence within lethal group 3 medulloblastoma

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