Ovarian tumor cells gain competitive advantage by actively reducing the cellular fitness of microenvironment cells

Esha Madan; António M. Palma; Vignesh Vudatha; Amit Kumar; Praveen Bhoopathi; Jochen Wilhelm; Tytus Bernas; Patrick C. Martin; Gaurav Bilolikar; Aenya Gogna; Maria Leonor Peixoto; Isabelle Dreier; Thais Fenz Araujo; Elena Garre; Anna Gustafsson; Kalpana Deepa Priya Dorayappan; Narsimha Mamidi; Zhaoyu Sun; Michail Yekelchyk; Davide Accardi; Amalie Lykke Olsen; Lin Lin; Asaf Ashkenazy Titelman; Michael Bianchi; Phil Jessmon; Elnaz Abbasi Farid; Anjan K. Pradhan; Lena Neufeld; Eilam Yeini; Santanu Maji; Christopher J. Pelham; Hyobin Kim; Daniel Oh; Hans Olav Rolfsnes; Rita C. Marques; Amy Lu; Masaki Nagane; Sahil Chaudhary; Kartik Gupta; Keshav C. Gogna; Ana Bigio; Karthikeya Bhoopathi; Padmanabhan Mannangatti; K. Gopinath Achary; Javed Akhtar; Sara Belião; Swadesh Das; Isabel Correia; Cláudia L. da Silva; Arsénio M. Fialho; Michael J. Poellmann; Kaila Javius-Jones; Adam M. Hawkridge; Sanya Pal; Kumari S. Shree; Emad A. Rakha; Sambhav Khurana; Gaoping Xiao; Dongyu Zhang; Arjun Rijal; Charles Lyons; Steven R. Grossman; David P. Turner; Raghavendra Pillappa; Karanvir Prakash; Gaurav Gupta; Gary L.W.G. Robinson; Jennifer Koblinski; Hongjun Wang; Gita Singh; Sujay Singh; Sagar Rayamajhi; Manny D. Bacolod; Hope Richards; Sadia Sayeed; Katherine P. Klein; David Chelmow; Ronit Satchi-Fainaro; Karuppaiyah Selvendiran; Denise Connolly; Frits Alan Thorsen; Rolf Bjerkvig; Kenneth P. Nephew; Michael O. Idowu; Mark P. Kühnel; Christopher Moskaluk; Seungpyo Hong; William L. Redmond; Göran Landberg; Antonio Lopez-Beltran; Andrew S. Poklepovic; Arun Sanyal; Paul B. Fisher; George M. Church; Usha Menon; Ronny Drapkin; Andrew K. Godwin; Yonglun Luo; Maximilian Ackermann; Alexandar Tzankov; Kirsten D. Mertz; Danny Jonigk; Allan Tsung; David Sidransky; Jose Trevino; Arturo P. Saavedra; Robert Winn; Kyoung Jae Won; Eduardo Moreno; Rajan Gogna

doi:10.1038/s41587-024-02453-3

Ovarian tumor cells gain competitive advantage by actively reducing the cellular fitness of microenvironment cells

Esha Madan^*, António M. Palma, Vignesh Vudatha, Amit Kumar, Praveen Bhoopathi, Jochen Wilhelm, Tytus Bernas, Patrick C. Martin, Gaurav Bilolikar, Aenya Gogna, Maria Leonor Peixoto, Isabelle Dreier, Thais Fenz Araujo, Elena Garre, Anna Gustafsson, Kalpana Deepa Priya Dorayappan, Narsimha Mamidi, Zhaoyu Sun, Michail Yekelchyk, Davide AccardiAmalie Lykke Olsen, Lin Lin, Asaf Ashkenazy Titelman, Michael Bianchi, Phil Jessmon, Elnaz Abbasi Farid, Anjan K. Pradhan, Lena Neufeld, Eilam Yeini, Santanu Maji, Christopher J. Pelham, Hyobin Kim, Daniel Oh, Hans Olav Rolfsnes, Rita C. Marques, Amy Lu, Masaki Nagane, Sahil Chaudhary, Kartik Gupta, Keshav C. Gogna, Ana Bigio, Karthikeya Bhoopathi, Padmanabhan Mannangatti, K. Gopinath Achary, Javed Akhtar, Sara Belião, Swadesh Das, Isabel Correia, Cláudia L. da Silva, Arsénio M. Fialho, Michael J. Poellmann, Kaila Javius-Jones, Adam M. Hawkridge, Sanya Pal, Kumari S. Shree, Emad A. Rakha, Sambhav Khurana, Gaoping Xiao, Dongyu Zhang, Arjun Rijal, Charles Lyons, Steven R. Grossman, David P. Turner, Raghavendra Pillappa, Karanvir Prakash, Gaurav Gupta, Gary L.W.G. Robinson, Jennifer Koblinski, Hongjun Wang, Gita Singh, Sujay Singh, Sagar Rayamajhi, Manny D. Bacolod, Hope Richards, Sadia Sayeed, Katherine P. Klein, David Chelmow, Ronit Satchi-Fainaro, Karuppaiyah Selvendiran, Denise Connolly, Frits Alan Thorsen, Rolf Bjerkvig, Kenneth P. Nephew, Michael O. Idowu, Mark P. Kühnel, Christopher Moskaluk, Seungpyo Hong, William L. Redmond, Göran Landberg, Antonio Lopez-Beltran, Andrew S. Poklepovic, Arun Sanyal, Paul B. Fisher, George M. Church, Usha Menon, Ronny Drapkin, Andrew K. Godwin, Yonglun Luo, Maximilian Ackermann, Alexandar Tzankov, Kirsten D. Mertz, Danny Jonigk, Allan Tsung, David Sidransky, Jose Trevino, Arturo P. Saavedra, Robert Winn, Kyoung Jae Won, Eduardo Moreno, Rajan Gogna^*

^*Corresponding author for this work

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

2 Scopus citations

Abstract

Cell competition and fitness comparison between cancer and tumor microenvironment (TME) cells determine oncogenic fate. Our previous study established a role for human Flower isoforms as fitness fingerprints, where the expression of Flower Win isoforms in tumor cells leads to growth advantage over TME cells expressing Lose isoforms. Here we demonstrate that the expression of Flower Lose and reduced microenvironment fitness is not a pre-existing condition but, rather, a cancer-induced phenomenon. Cancer cells actively reduce TME fitness by the exosome-mediated release of a cancer-specific long non-coding RNA, Tu-Stroma, which controls the splicing of the Flower gene in the TME cells and expression of Flower Lose isoform, which leads to reduced fitness status. This mechanism controls cancer growth, metastasis and host survival in ovarian cancer. Targeting Flower protein with humanized monoclonal antibody (mAb) in mice significantly reduces cancer growth and metastasis and improves survival. Pre-treatment with Flower mAb protects intraperitoneal organs from developing lesions despite the presence of aggressive tumor cells.

Original language	English
Article number	e13714
Journal	Nature Biotechnology
DOIs	https://doi.org/10.1038/s41587-024-02453-3
State	Accepted/In press - 2024
Externally published	Yes

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10.1038/s41587-024-02453-3

Cite this

Madan, E., Palma, A. M., Vudatha, V., Kumar, A., Bhoopathi, P., Wilhelm, J., Bernas, T., Martin, P. C., Bilolikar, G., Gogna, A., Peixoto, M. L., Dreier, I., Araujo, T. F., Garre, E., Gustafsson, A., Dorayappan, K. D. P., Mamidi, N., Sun, Z., Yekelchyk, M., ... Gogna, R. (Accepted/In press). Ovarian tumor cells gain competitive advantage by actively reducing the cellular fitness of microenvironment cells. Nature Biotechnology, Article e13714. https://doi.org/10.1038/s41587-024-02453-3

@article{b51cb19a9e004cb5a6ea5805c797e83f,

title = "Ovarian tumor cells gain competitive advantage by actively reducing the cellular fitness of microenvironment cells",

abstract = "Cell competition and fitness comparison between cancer and tumor microenvironment (TME) cells determine oncogenic fate. Our previous study established a role for human Flower isoforms as fitness fingerprints, where the expression of Flower Win isoforms in tumor cells leads to growth advantage over TME cells expressing Lose isoforms. Here we demonstrate that the expression of Flower Lose and reduced microenvironment fitness is not a pre-existing condition but, rather, a cancer-induced phenomenon. Cancer cells actively reduce TME fitness by the exosome-mediated release of a cancer-specific long non-coding RNA, Tu-Stroma, which controls the splicing of the Flower gene in the TME cells and expression of Flower Lose isoform, which leads to reduced fitness status. This mechanism controls cancer growth, metastasis and host survival in ovarian cancer. Targeting Flower protein with humanized monoclonal antibody (mAb) in mice significantly reduces cancer growth and metastasis and improves survival. Pre-treatment with Flower mAb protects intraperitoneal organs from developing lesions despite the presence of aggressive tumor cells.",

author = "Esha Madan and Palma, {Ant{\'o}nio M.} and Vignesh Vudatha and Amit Kumar and Praveen Bhoopathi and Jochen Wilhelm and Tytus Bernas and Martin, {Patrick C.} and Gaurav Bilolikar and Aenya Gogna and Peixoto, {Maria Leonor} and Isabelle Dreier and Araujo, {Thais Fenz} and Elena Garre and Anna Gustafsson and Dorayappan, {Kalpana Deepa Priya} and Narsimha Mamidi and Zhaoyu Sun and Michail Yekelchyk and Davide Accardi and Olsen, {Amalie Lykke} and Lin Lin and Titelman, {Asaf Ashkenazy} and Michael Bianchi and Phil Jessmon and Farid, {Elnaz Abbasi} and Pradhan, {Anjan K.} and Lena Neufeld and Eilam Yeini and Santanu Maji and Pelham, {Christopher J.} and Hyobin Kim and Daniel Oh and Rolfsnes, {Hans Olav} and Marques, {Rita C.} and Amy Lu and Masaki Nagane and Sahil Chaudhary and Kartik Gupta and Gogna, {Keshav C.} and Ana Bigio and Karthikeya Bhoopathi and Padmanabhan Mannangatti and Achary, {K. Gopinath} and Javed Akhtar and Sara Beli{\~a}o and Swadesh Das and Isabel Correia and {da Silva}, {Cl{\'a}udia L.} and Fialho, {Ars{\'e}nio M.} and Poellmann, {Michael J.} and Kaila Javius-Jones and Hawkridge, {Adam M.} and Sanya Pal and Shree, {Kumari S.} and Rakha, {Emad A.} and Sambhav Khurana and Gaoping Xiao and Dongyu Zhang and Arjun Rijal and Charles Lyons and Grossman, {Steven R.} and Turner, {David P.} and Raghavendra Pillappa and Karanvir Prakash and Gaurav Gupta and Robinson, {Gary L.W.G.} and Jennifer Koblinski and Hongjun Wang and Gita Singh and Sujay Singh and Sagar Rayamajhi and Bacolod, {Manny D.} and Hope Richards and Sadia Sayeed and Klein, {Katherine P.} and David Chelmow and Ronit Satchi-Fainaro and Karuppaiyah Selvendiran and Denise Connolly and Thorsen, {Frits Alan} and Rolf Bjerkvig and Nephew, {Kenneth P.} and Idowu, {Michael O.} and K{\"u}hnel, {Mark P.} and Christopher Moskaluk and Seungpyo Hong and Redmond, {William L.} and G{\"o}ran Landberg and Antonio Lopez-Beltran and Poklepovic, {Andrew S.} and Arun Sanyal and Fisher, {Paul B.} and Church, {George M.} and Usha Menon and Ronny Drapkin and Godwin, {Andrew K.} and Yonglun Luo and Maximilian Ackermann and Alexandar Tzankov and Mertz, {Kirsten D.} and Danny Jonigk and Allan Tsung and David Sidransky and Jose Trevino and Saavedra, {Arturo P.} and Robert Winn and Won, {Kyoung Jae} and Eduardo Moreno and Rajan Gogna",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",

year = "2024",

doi = "10.1038/s41587-024-02453-3",

language = "English",

journal = "Nature Biotechnology",

issn = "1087-0156",

}

Madan, E, Palma, AM, Vudatha, V, Kumar, A, Bhoopathi, P, Wilhelm, J, Bernas, T, Martin, PC, Bilolikar, G, Gogna, A, Peixoto, ML, Dreier, I, Araujo, TF, Garre, E, Gustafsson, A, Dorayappan, KDP, Mamidi, N, Sun, Z, Yekelchyk, M, Accardi, D, Olsen, AL, Lin, L, Titelman, AA, Bianchi, M, Jessmon, P, Farid, EA, Pradhan, AK, Neufeld, L, Yeini, E, Maji, S, Pelham, CJ, Kim, H, Oh, D, Rolfsnes, HO, Marques, RC, Lu, A, Nagane, M, Chaudhary, S, Gupta, K, Gogna, KC, Bigio, A, Bhoopathi, K, Mannangatti, P, Achary, KG, Akhtar, J, Belião, S, Das, S, Correia, I, da Silva, CL, Fialho, AM, Poellmann, MJ, Javius-Jones, K, Hawkridge, AM, Pal, S, Shree, KS, Rakha, EA, Khurana, S, Xiao, G, Zhang, D, Rijal, A, Lyons, C, Grossman, SR, Turner, DP, Pillappa, R, Prakash, K, Gupta, G, Robinson, GLWG, Koblinski, J, Wang, H, Singh, G, Singh, S, Rayamajhi, S, Bacolod, MD, Richards, H, Sayeed, S, Klein, KP, Chelmow, D, Satchi-Fainaro, R, Selvendiran, K, Connolly, D, Thorsen, FA, Bjerkvig, R, Nephew, KP, Idowu, MO, Kühnel, MP, Moskaluk, C, Hong, S, Redmond, WL, Landberg, G, Lopez-Beltran, A, Poklepovic, AS, Sanyal, A, Fisher, PB, Church, GM, Menon, U, Drapkin, R, Godwin, AK, Luo, Y, Ackermann, M, Tzankov, A, Mertz, KD, Jonigk, D, Tsung, A, Sidransky, D, Trevino, J, Saavedra, AP, Winn, R, Won, KJ, Moreno, E & Gogna, R 2024, 'Ovarian tumor cells gain competitive advantage by actively reducing the cellular fitness of microenvironment cells', Nature Biotechnology. https://doi.org/10.1038/s41587-024-02453-3

TY - JOUR

T1 - Ovarian tumor cells gain competitive advantage by actively reducing the cellular fitness of microenvironment cells

AU - Madan, Esha

AU - Palma, António M.

AU - Vudatha, Vignesh

AU - Kumar, Amit

AU - Bhoopathi, Praveen

AU - Wilhelm, Jochen

AU - Bernas, Tytus

AU - Martin, Patrick C.

AU - Bilolikar, Gaurav

AU - Gogna, Aenya

AU - Peixoto, Maria Leonor

AU - Dreier, Isabelle

AU - Araujo, Thais Fenz

AU - Garre, Elena

AU - Gustafsson, Anna

AU - Dorayappan, Kalpana Deepa Priya

AU - Mamidi, Narsimha

AU - Sun, Zhaoyu

AU - Yekelchyk, Michail

AU - Accardi, Davide

AU - Olsen, Amalie Lykke

AU - Lin, Lin

AU - Titelman, Asaf Ashkenazy

AU - Bianchi, Michael

AU - Jessmon, Phil

AU - Farid, Elnaz Abbasi

AU - Pradhan, Anjan K.

AU - Neufeld, Lena

AU - Yeini, Eilam

AU - Maji, Santanu

AU - Pelham, Christopher J.

AU - Kim, Hyobin

AU - Oh, Daniel

AU - Rolfsnes, Hans Olav

AU - Marques, Rita C.

AU - Lu, Amy

AU - Nagane, Masaki

AU - Chaudhary, Sahil

AU - Gupta, Kartik

AU - Gogna, Keshav C.

AU - Bigio, Ana

AU - Bhoopathi, Karthikeya

AU - Mannangatti, Padmanabhan

AU - Achary, K. Gopinath

AU - Akhtar, Javed

AU - Belião, Sara

AU - Das, Swadesh

AU - Correia, Isabel

AU - da Silva, Cláudia L.

AU - Fialho, Arsénio M.

AU - Poellmann, Michael J.

AU - Javius-Jones, Kaila

AU - Hawkridge, Adam M.

AU - Pal, Sanya

AU - Shree, Kumari S.

AU - Rakha, Emad A.

AU - Khurana, Sambhav

AU - Xiao, Gaoping

AU - Zhang, Dongyu

AU - Rijal, Arjun

AU - Lyons, Charles

AU - Grossman, Steven R.

AU - Turner, David P.

AU - Pillappa, Raghavendra

AU - Prakash, Karanvir

AU - Gupta, Gaurav

AU - Robinson, Gary L.W.G.

AU - Koblinski, Jennifer

AU - Wang, Hongjun

AU - Singh, Gita

AU - Singh, Sujay

AU - Rayamajhi, Sagar

AU - Bacolod, Manny D.

AU - Richards, Hope

AU - Sayeed, Sadia

AU - Klein, Katherine P.

AU - Chelmow, David

AU - Satchi-Fainaro, Ronit

AU - Selvendiran, Karuppaiyah

AU - Connolly, Denise

AU - Thorsen, Frits Alan

AU - Bjerkvig, Rolf

AU - Nephew, Kenneth P.

AU - Idowu, Michael O.

AU - Kühnel, Mark P.

AU - Moskaluk, Christopher

AU - Hong, Seungpyo

AU - Redmond, William L.

AU - Landberg, Göran

AU - Lopez-Beltran, Antonio

AU - Poklepovic, Andrew S.

AU - Sanyal, Arun

AU - Fisher, Paul B.

AU - Church, George M.

AU - Menon, Usha

AU - Drapkin, Ronny

AU - Godwin, Andrew K.

AU - Luo, Yonglun

AU - Ackermann, Maximilian

AU - Tzankov, Alexandar

AU - Mertz, Kirsten D.

AU - Jonigk, Danny

AU - Tsung, Allan

AU - Sidransky, David

AU - Trevino, Jose

AU - Saavedra, Arturo P.

AU - Winn, Robert

AU - Won, Kyoung Jae

AU - Moreno, Eduardo

AU - Gogna, Rajan

PY - 2024

Y1 - 2024

N2 - Cell competition and fitness comparison between cancer and tumor microenvironment (TME) cells determine oncogenic fate. Our previous study established a role for human Flower isoforms as fitness fingerprints, where the expression of Flower Win isoforms in tumor cells leads to growth advantage over TME cells expressing Lose isoforms. Here we demonstrate that the expression of Flower Lose and reduced microenvironment fitness is not a pre-existing condition but, rather, a cancer-induced phenomenon. Cancer cells actively reduce TME fitness by the exosome-mediated release of a cancer-specific long non-coding RNA, Tu-Stroma, which controls the splicing of the Flower gene in the TME cells and expression of Flower Lose isoform, which leads to reduced fitness status. This mechanism controls cancer growth, metastasis and host survival in ovarian cancer. Targeting Flower protein with humanized monoclonal antibody (mAb) in mice significantly reduces cancer growth and metastasis and improves survival. Pre-treatment with Flower mAb protects intraperitoneal organs from developing lesions despite the presence of aggressive tumor cells.

AB - Cell competition and fitness comparison between cancer and tumor microenvironment (TME) cells determine oncogenic fate. Our previous study established a role for human Flower isoforms as fitness fingerprints, where the expression of Flower Win isoforms in tumor cells leads to growth advantage over TME cells expressing Lose isoforms. Here we demonstrate that the expression of Flower Lose and reduced microenvironment fitness is not a pre-existing condition but, rather, a cancer-induced phenomenon. Cancer cells actively reduce TME fitness by the exosome-mediated release of a cancer-specific long non-coding RNA, Tu-Stroma, which controls the splicing of the Flower gene in the TME cells and expression of Flower Lose isoform, which leads to reduced fitness status. This mechanism controls cancer growth, metastasis and host survival in ovarian cancer. Targeting Flower protein with humanized monoclonal antibody (mAb) in mice significantly reduces cancer growth and metastasis and improves survival. Pre-treatment with Flower mAb protects intraperitoneal organs from developing lesions despite the presence of aggressive tumor cells.

UR - http://www.scopus.com/inward/record.url?scp=85211941313&partnerID=8YFLogxK

U2 - 10.1038/s41587-024-02453-3

DO - 10.1038/s41587-024-02453-3

M3 - Article

AN - SCOPUS:85211941313

SN - 1087-0156

JO - Nature Biotechnology

JF - Nature Biotechnology

M1 - e13714

ER -