Macrovascular tumor infiltration and circulating tumor cell cluster dynamics in patients with cancer approaching the end of life

Kelley Newcomer; Alessandro Bifolco; Sarah Reeves; Giada Pontecorvi; Simran Asawa; Magdalena K. Sznurkowska; Manuel Nüesch; Lauren L. Ozimski; Louisa Bolm; Malte Maria Sieren; Lukas Müller; Zhikai Chi; William Gasper; Megan B. Wachsmann; William Moore; Xue Zheng; Angelique Fokkema; Alexander Ring; Bich Doan Nguyen-Sträuli; Selina Budinjas; Meike ten Winkel; Benedikt Färber; Abbas Zaki; Nafeesah Fatimah; Elena Crecca; John D. Karalis; Raghav Chandra; Hillary Prince; Kristina L. Goff; Sung Hee Choi; Carol Abousaab; Song Zhang; Suzanne Cole; Kathryn Naumann; Tobias Keck; Patricio M. Polanco; Ana Gvozdenovic; Ilona Krol; Francesc Castro-Giner; Carlos Arteaga; Herbert J. Zeh; Roman Kloeckner; Dario Ghersi; Nicola Aceto; Matteo Ligorio

doi:10.1038/s41591-025-03966-3

Macrovascular tumor infiltration and circulating tumor cell cluster dynamics in patients with cancer approaching the end of life

Kelley Newcomer, Alessandro Bifolco, Sarah Reeves, Giada Pontecorvi, Simran Asawa, Magdalena K. Sznurkowska, Manuel Nüesch, Lauren L. Ozimski, Louisa Bolm, Malte Maria Sieren, Lukas Müller, Zhikai Chi, William Gasper, Megan B. Wachsmann, William Moore, Xue Zheng, Angelique Fokkema, Alexander Ring, Bich Doan Nguyen-Sträuli, Selina BudinjasMeike ten Winkel, Benedikt Färber, Abbas Zaki, Nafeesah Fatimah, Elena Crecca, John D. Karalis, Raghav Chandra, Hillary Prince, Kristina L. Goff, Sung Hee Choi, Carol Abousaab, Song Zhang, Suzanne Cole, Kathryn Naumann, Tobias Keck, Patricio M. Polanco, Ana Gvozdenovic, Ilona Krol, Francesc Castro-Giner, Carlos Arteaga, Herbert J. Zeh, Roman Kloeckner, Dario Ghersi, Nicola Aceto^*, Matteo Ligorio^*

^*Korrespondierende/r Autor/-in für diese Arbeit

6 Zitate (Scopus)

Abstract

End-of-life events related to carcinoma lethality are poorly characterized. Herein we conducted an observational, prospective, case–control study enrolling 21 patients with solid tumors and 10 patients without known malignancy, complemented by a retrospective validation cohort of 1,250 patients with cancer. In our prospective cohort, we observed spikes in circulating tumor cell (CTC) counts, particularly clusters, immediately before death (P < 0.0001), as well as pathological evidence of macrovascular infiltration and large-vessel occlusion obtained through rapid autopsy. In the validation cohort, radiological evidence of macrovascular infiltration emerged as the strongest predictor of poor survival—independent of metastasis—in treatment-homogeneous patients with colorectal, lung, ovarian, hepatocellular or pancreatic cancer (hazard ratios = 4.0–22.4). Collectively, these findings suggest that macrovascular infiltration and spikes in CTC clusters with consequent vascular failure could be pivotal end-of-life events associated with cancer lethality, providing a rationale for future trials aimed at curbing infiltration into large vessels.

Originalsprache	Englisch
Zeitschrift	Nature Medicine
Jahrgang	31
Ausgabenummer	12
Seiten (von - bis)	4140-4149
Seitenumfang	10
ISSN	1078-8956
DOIs	https://doi.org/10.1038/s41591-025-03966-3
Publikationsstatus	Veröffentlicht - 12.2025

Fördermittel

Research in the Ligorio laboratory is supported by the Cancer Prevention & Research of Texas Recruitment of First-Time Tenure-Track Faculty Members Grant (RR200023), an R37 National Institute of Health Cancer Institute Grant (5R37CA242070), American-Italian Cancer Foundation Post-Doctoral Research Fellowship to Giada Pontecorvi, PhD (2022–2024), and the Department of Surgery and the Harold C. Simmons Comprehensive Cancer Center at UTSW Medical Center. A special thanks to the current and previous members of the Ligorio laboratory, as well as R. Hammer, S. Comerford, R. Napier, C. Lewis, R. Nix, T. Harris and C. Rodriguez, for their support. Research in the Aceto laboratory is supported by the European Research Council (101001652), the strategic focus area of Personalized Health and Related Technologies at ETH Zurich (PHRT-960), the Swiss National Science Foundation (212183), the Swiss Cancer League (KLS-5636-08-2022), the ETH Lymphoma Challenge (LC-02-22) and ETH Zürich. We acknowledge the assistance of the University of Texas Southwestern Tissue Management Shared Resource, a shared resource at the Simmons Comprehensive Cancer Center, which is supported in part by the National Cancer Institute (award P30 CA142543). We would also like to thank the UTSW Willed Body Program, as well as Visiting Nurse Association Hospice of Texas, Faith Presbyterian Hospice and Pathway Hospice for their partnership on this project and for hospice patients and their families.

Träger	Trägernummer
Faith Presbyterian Hospice and Pathway Hospice
Visiting Nurse Association Hospice of Texas
Department of Surgery
American-Italian Cancer Foundation
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	212183
Eidgenössische Technische Hochschule Zürich	PHRT-960
National Cancer Institute	5R37CA242070, P30 CA142543
European Research Council	101001652
Krebsliga Schweiz	KLS-5636-08-2022, LC-02-22

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Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Profilbereich: Lübeck Integrated Oncology Network (LION)
Forschungsschwerpunkt: Biomedizintechnik

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2.22-14 Hämatologie, Onkologie
2.22-25 Allgemein- und Viszeralchirurgie
2.22-30 Radiologie

Dokumente

10.1038/s41591-025-03966-3

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Newcomer, K., Bifolco, A., Reeves, S., Pontecorvi, G., Asawa, S., Sznurkowska, M. K., Nüesch, M., Ozimski, L. L., Bolm, L., Sieren, M. M., Müller, L., Chi, Z., Gasper, W., Wachsmann, M. B., Moore, W., Zheng, X., Fokkema, A., Ring, A., Nguyen-Sträuli, B. D., ... Ligorio, M. (2025). Macrovascular tumor infiltration and circulating tumor cell cluster dynamics in patients with cancer approaching the end of life. Nature Medicine, 31(12), 4140-4149. https://doi.org/10.1038/s41591-025-03966-3

@article{53a39e7b051f40cf870cd3a3865d9b42,

title = "Macrovascular tumor infiltration and circulating tumor cell cluster dynamics in patients with cancer approaching the end of life",

abstract = "End-of-life events related to carcinoma lethality are poorly characterized. Herein we conducted an observational, prospective, case–control study enrolling 21 patients with solid tumors and 10 patients without known malignancy, complemented by a retrospective validation cohort of 1,250 patients with cancer. In our prospective cohort, we observed spikes in circulating tumor cell (CTC) counts, particularly clusters, immediately before death (P < 0.0001), as well as pathological evidence of macrovascular infiltration and large-vessel occlusion obtained through rapid autopsy. In the validation cohort, radiological evidence of macrovascular infiltration emerged as the strongest predictor of poor survival—independent of metastasis—in treatment-homogeneous patients with colorectal, lung, ovarian, hepatocellular or pancreatic cancer (hazard ratios = 4.0–22.4). Collectively, these findings suggest that macrovascular infiltration and spikes in CTC clusters with consequent vascular failure could be pivotal end-of-life events associated with cancer lethality, providing a rationale for future trials aimed at curbing infiltration into large vessels.",

author = "Kelley Newcomer and Alessandro Bifolco and Sarah Reeves and Giada Pontecorvi and Simran Asawa and Sznurkowska, \{Magdalena K.\} and Manuel N{\"u}esch and Ozimski, \{Lauren L.\} and Louisa Bolm and Sieren, \{Malte Maria\} and Lukas M{\"u}ller and Zhikai Chi and William Gasper and Wachsmann, \{Megan B.\} and William Moore and Xue Zheng and Angelique Fokkema and Alexander Ring and Nguyen-Str{\"a}uli, \{Bich Doan\} and Selina Budinjas and \{ten Winkel\}, Meike and Benedikt F{\"a}rber and Abbas Zaki and Nafeesah Fatimah and Elena Crecca and Karalis, \{John D.\} and Raghav Chandra and Hillary Prince and Goff, \{Kristina L.\} and Choi, \{Sung Hee\} and Carol Abousaab and Song Zhang and Suzanne Cole and Kathryn Naumann and Tobias Keck and Polanco, \{Patricio M.\} and Ana Gvozdenovic and Ilona Krol and Francesc Castro-Giner and Carlos Arteaga and Zeh, \{Herbert J.\} and Roman Kloeckner and Dario Ghersi and Nicola Aceto and Matteo Ligorio",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = dec,

doi = "10.1038/s41591-025-03966-3",

language = "English",

volume = "31",

pages = "4140--4149",

journal = "Nature Medicine",

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Newcomer, K, Bifolco, A, Reeves, S, Pontecorvi, G, Asawa, S, Sznurkowska, MK, Nüesch, M, Ozimski, LL, Bolm, L , Sieren, MM, Müller, L, Chi, Z, Gasper, W, Wachsmann, MB, Moore, W, Zheng, X, Fokkema, A, Ring, A, Nguyen-Sträuli, BD, Budinjas, S, ten Winkel, M , Färber, B, Zaki, A, Fatimah, N, Crecca, E, Karalis, JD, Chandra, R, Prince, H, Goff, KL, Choi, SH, Abousaab, C, Zhang, S, Cole, S, Naumann, K, Keck, T, Polanco, PM, Gvozdenovic, A, Krol, I, Castro-Giner, F, Arteaga, C, Zeh, HJ, Kloeckner, R, Ghersi, D, Aceto, N & Ligorio, M 2025, 'Macrovascular tumor infiltration and circulating tumor cell cluster dynamics in patients with cancer approaching the end of life', Nature Medicine, Jg. 31, Nr. 12, S. 4140-4149. https://doi.org/10.1038/s41591-025-03966-3

TY - JOUR

T1 - Macrovascular tumor infiltration and circulating tumor cell cluster dynamics in patients with cancer approaching the end of life

AU - Newcomer, Kelley

AU - Bifolco, Alessandro

AU - Reeves, Sarah

AU - Pontecorvi, Giada

AU - Asawa, Simran

AU - Sznurkowska, Magdalena K.

AU - Nüesch, Manuel

AU - Ozimski, Lauren L.

AU - Bolm, Louisa

AU - Sieren, Malte Maria

AU - Müller, Lukas

AU - Chi, Zhikai

AU - Gasper, William

AU - Wachsmann, Megan B.

AU - Moore, William

AU - Zheng, Xue

AU - Fokkema, Angelique

AU - Ring, Alexander

AU - Nguyen-Sträuli, Bich Doan

AU - Budinjas, Selina

AU - ten Winkel, Meike

AU - Färber, Benedikt

AU - Zaki, Abbas

AU - Fatimah, Nafeesah

AU - Crecca, Elena

AU - Karalis, John D.

AU - Chandra, Raghav

AU - Prince, Hillary

AU - Goff, Kristina L.

AU - Choi, Sung Hee

AU - Abousaab, Carol

AU - Zhang, Song

AU - Cole, Suzanne

AU - Naumann, Kathryn

AU - Keck, Tobias

AU - Polanco, Patricio M.

AU - Gvozdenovic, Ana

AU - Krol, Ilona

AU - Castro-Giner, Francesc

AU - Arteaga, Carlos

AU - Zeh, Herbert J.

AU - Kloeckner, Roman

AU - Ghersi, Dario

AU - Aceto, Nicola

AU - Ligorio, Matteo

PY - 2025/12

Y1 - 2025/12

N2 - End-of-life events related to carcinoma lethality are poorly characterized. Herein we conducted an observational, prospective, case–control study enrolling 21 patients with solid tumors and 10 patients without known malignancy, complemented by a retrospective validation cohort of 1,250 patients with cancer. In our prospective cohort, we observed spikes in circulating tumor cell (CTC) counts, particularly clusters, immediately before death (P < 0.0001), as well as pathological evidence of macrovascular infiltration and large-vessel occlusion obtained through rapid autopsy. In the validation cohort, radiological evidence of macrovascular infiltration emerged as the strongest predictor of poor survival—independent of metastasis—in treatment-homogeneous patients with colorectal, lung, ovarian, hepatocellular or pancreatic cancer (hazard ratios = 4.0–22.4). Collectively, these findings suggest that macrovascular infiltration and spikes in CTC clusters with consequent vascular failure could be pivotal end-of-life events associated with cancer lethality, providing a rationale for future trials aimed at curbing infiltration into large vessels.

AB - End-of-life events related to carcinoma lethality are poorly characterized. Herein we conducted an observational, prospective, case–control study enrolling 21 patients with solid tumors and 10 patients without known malignancy, complemented by a retrospective validation cohort of 1,250 patients with cancer. In our prospective cohort, we observed spikes in circulating tumor cell (CTC) counts, particularly clusters, immediately before death (P < 0.0001), as well as pathological evidence of macrovascular infiltration and large-vessel occlusion obtained through rapid autopsy. In the validation cohort, radiological evidence of macrovascular infiltration emerged as the strongest predictor of poor survival—independent of metastasis—in treatment-homogeneous patients with colorectal, lung, ovarian, hepatocellular or pancreatic cancer (hazard ratios = 4.0–22.4). Collectively, these findings suggest that macrovascular infiltration and spikes in CTC clusters with consequent vascular failure could be pivotal end-of-life events associated with cancer lethality, providing a rationale for future trials aimed at curbing infiltration into large vessels.

UR - https://www.scopus.com/pages/publications/105018813474

U2 - 10.1038/s41591-025-03966-3

DO - 10.1038/s41591-025-03966-3

M3 - Journal articles

C2 - 41102560

AN - SCOPUS:105018813474

SN - 1078-8956

VL - 31

SP - 4140

EP - 4149

JO - Nature Medicine

JF - Nature Medicine

IS - 12

ER -

Macrovascular tumor infiltration and circulating tumor cell cluster dynamics in patients with cancer approaching the end of life

Abstract

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Strategische Forschungsbereiche und Zentren

DFG-Fachsystematik

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